TW202408996A - 3,4-dihydroquinoline-2(1h)-one compound - Google Patents

Abstract

The subject of the present invention is to provide novel compounds having thyroid stimulating hormone receptor antagonist activity and useful for the treatment of thyroid-related diseases. The present invention relates to a 3,4-dihydroquinolin-2(1H)-one compound represented by the following formula (I) or a pharmacologically acceptable salt thereof. The compound of the present invention or a pharmacologically acceptable salt thereof has antagonist activity against thyroid stimulating hormone receptors and is useful as a therapeutic agent for thyroid-related diseases (e.g., hyperthyroidism, Graves' disease, thyroid eye lesions, and thyroid cancer).

Description

3,4-Dihydroquinolin-2(1H)-one compound

The present invention relates to 3,4-dihydroquinolin-2(1H)-one compounds useful as pharmaceuticals. More specifically, the present invention relates to a 3,4-dihydroquinolin-2(1H)-one compound that has antagonistic activity against thyroid stimulating hormone receptor (TSHR) and can be used as a therapeutic agent for thyroid-related diseases, or its pharmacology Learn as much salt as you allow.

Triiodothyronine (T3) or thyroxine (T4), which are thyroid hormones, play an important role in production, growth, and metabolism. Their synthesis is tightly regulated by thyroid stimulating hormone (TSH) secreted from the pituitary gland. ,secretion.

Hyperthyroidism is the excessive secretion of thyroid hormones for some reason, and due to the action of this hormone, thyroid enlargement, tachycardia, high blood pressure, fatigue, weight loss, palpitations, sleep disorders, and irregular menstruation occur in the body and mind. and other adverse effects.

There are various causes of hyperthyroidism, the most common of which is Graves' disease (Basedow's disease). Graves' disease is caused by an autoimmune mechanism that treats the own thyroid gland as a foreign body and produces autoantibodies, so-called TSHR antibodies (TRAb), against TSHR present in thyroid follicular epithelial cells. This TRAb acts as an agonist on TSHR and excessively stimulates TSHR, so thyroid stimulating hormone is secreted as needed, causing the onset of hyperthyroidism.

In addition, thyroid eye disease is also known to accompany Graves' disease. Thyroid ophthalmopathy is an autoimmune inflammatory disease that manifests various eye disease symptoms. It is generally believed that the main reason is the stimulating effect of TRAb on the TSHR of orbital tissue. Most of them occur at about the same time as hyperthyroidism, but there are also cases where they are not accompanied by thyroid dysfunction.

At present, the drug treatment for Graves' disease is to use antithyroid drugs such as thiamazole or propylthiouracil that inhibit the biosynthesis of thyroid stimulating hormone, but there are problems such as low remission rate, long treatment period until remission, and high frequency of side effects. Therefore, there is still a desire for a treatment for Graves' disease with a novel mechanism of action.

When TSHR is blocked or signal transduction induced by TSHR is inhibited, the production and secretion of thyroid stimulating hormone and the proliferation of thyroid cells are inhibited. Therefore, it is generally believed that TSHR antagonists have therapeutic effects on Graves' disease and thyroid eye disease caused by the agonistic effect of TRAb on TSHR (patent documents 1, 2). NCGC00242364 is known as a TSHR antagonist, and it has been shown that it has a blood T4 concentration-lowering effect on mice administered with TSH-releasing hormone (TRH) and mice administered with thyroid stimulating antibody M22 (non-patent document 1).

Compounds having TSHR antagonistic activity are described in Patent Documents 1 to 3 and Non-Patent Document 1. However, the 3,4-dihydroquinolin-2(1H)-one compound of the present invention is not described in Patent Documents 1 to 3 and Non-Patent Document 1. [Prior technical literature] [Patent Document]

[Patent Document 1] U.S. Patent Publication No. 2011/0172267 [Patent Document 2] U.S. Patent Publication No. 2012/0315217 [Patent Document 3] U.S. Patent Publication No. 2019/0134024 [Non-Patent Document]

Non-patent document 1: Susanne Neumann et al., "Endocrinology" 2014, Volume 155, No. 1, p.310-314

(Invent the problem you want to solve)

The subject of the present invention is to provide novel compounds with TSHR antagonist activity that can be used to treat thyroid-related diseases. (Technical means to solve the problem)

The present invention relates to a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof.

That is, the present invention relates to the following [1] to [15], etc. [1] A compound or a pharmacologically acceptable salt thereof, represented by formula (I); [wherein, Ring Z is a C _6-10 aryl group, a 5- or 6-membered heteroaryl group, a C _3-8 cycloalkyl group, or a 3-8-membered heterocycloalkyl group; X is -CHR ^x - or -O-; R ^x is a hydrogen atom or a C _1-6 alkyl group; V ¹ is =CR ^{V 1} - or =N-; V ² is =CR ^{V 2} - or =N-; V ³ is =CR ^{V 3} - or =N-; R ^{V 1} , R ^{V 2} , and R ^{V 3} are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen C _1-6 alkyl group, a hydroxyl C _1-6 alkyl group, a C _6-10 aryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkoxy group; W is -CH ₂ - or -NH-; R [ ₀₀₄₃ ] wherein ^R1 is a hydrogen atom or a _C1-6 alkyl group; ^R2 is a halogen atom, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogen _C1-6 alkyl group, a C1-6 alkoxy group, a halogen _C1-6 alkoxy group, a _C6-10 aryl _C1-6 alkyl group or a _C6-10 aryl _C1-6 alkoxy group; n is an integer from 0 to 3; when n is 2 or 3, each ^R2 may be the same or different; ^R3 is a hydrogen atom, a halogen atom, or a _C1-6 alkyl group; ^R4 is a _C1-6 alkyl group, a halogen _C1-6 alkyl group, ^{-NR5R5 '} , or a _C3-8 cycloalkyl group; ^R5 and R5 ^' are independently a hydrogen atom or a _C1-6 alkyl group]. [2] The compound of [1] or a pharmacologically acceptable salt thereof, which is represented by formula (II); [Chemical 2] [wherein, Ring Z is a C _6-10 aryl group, a 5- or 6-membered heteroaryl group, a C _3-8 cycloalkyl group, or a 3-8-membered heterocycloalkyl group; X is -CHR ^x - or -O-; R ^x is a hydrogen atom or a C _1-6 alkyl group; V ¹ is =CR ^{V 1} - or =N-; V ² is =CR ^{V 2} - or =N-; V ³ is =CR ^{V 3} - or =N-; R ^{V 1} , R ^{V 2} , and R ^{V 3} are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen C _1-6 alkyl group, a C _6-10 aryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkoxy group; W is -CH ₂ - or -NH-; R ¹ is a hydrogen atom or a C _{[ 3 ]} The compound _of [ ₁ ] or [ ^2] _above or a pharmacologically acceptable salt thereof, wherein _V1 is = _CRV1- ; ^V2 is =CRV2-; ^{V3 is =CRV3-; RV1, RV2 and RV3 have} _the ^same _meaning ^{as in [ 1 ] or} [2] above. [4] The compound or pharmacologically acceptable salt thereof as described in any one of [1] to [3] above, wherein ring Z is a C _6-10 aryl group. [5] The compound or pharmacologically acceptable salt thereof as described in any one of [1] to [4] above, represented by formula (III): [wherein, X is ^-CHRx- , or -O-; ^Rx is a hydrogen atom or a _C1-6 alkyl group; ^RV1 is a hydrogen atom, a halogen atom, a hydroxyl group, a _C1-6 alkyl group, a _C1-6 alkoxy group, a halogen _C1-6 alkyl group, a _C6-10 aryl _C1-6 alkyl group, or a _C6-10 aryl _C1-6 alkoxy group; ^R1 is a hydrogen atom or a _C1-6 alkyl group; ^R2 is a halogen atom, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogen _C1-6 alkyl group, a _C1-6 alkoxy group, a halogen _C1-6 alkoxy group, a _C6-10 aryl _C1-6 alkyl group, or a _C6-10 aryl _C1-6 alkoxy group; n is an integer from 0 to 3; when n is 2 or 3, each ^R2 may be the same or different from each other]. [6] A compound as described in any one of [1] to [5] above or a pharmacologically acceptable salt thereof, wherein: R ^V1 is a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, or a halogen C _1-6 alkyl group; R ¹ is a C _1-6 alkyl group; R ² is a halogen atom, a C _1-6 alkyl group, a halogen C _1-6 alkyl group, a C _1-6 alkoxy group, or a halogen C _1-6 alkoxy group. [7] A compound as described in any one of [1] to [3] above or a pharmacologically acceptable salt thereof, represented by formula (IV); [Chemical 4] [wherein, Ring Z is a C _6-10 aryl group, a 5- or 6-membered heteroaryl group, or a C _3-8 cycloalkyl group; X is -CHR ^x -, or -O-; R ^x is a hydrogen atom, or a C _1-6 alkyl group; ^RV1 is a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group, a halogen C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkoxy group; R ¹ is a C _1-6 alkyl group; R ² is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogen C _1-6 alkyl group, a C _1-6 alkoxy group, or a halogen C _1-6 alkoxy group; n is an integer from 0 to 3; when n is 2 or 3, each R ² may be the same or different from each other]. [8] The compound of [7] above or a pharmacologically acceptable salt thereof, wherein ring Z is a C _6-10 aryl group. [9] The compound of any one of [1] to [8] above or a pharmacologically acceptable salt thereof, wherein X is -O-. [10] The compound of any one of [1] to [9] above or a pharmacologically acceptable salt thereof, selected from the group consisting of the following compounds; [Chemical 5] [Chemistry 6] and [Chemistry 7] [11] The compound or pharmacologically acceptable salt thereof of any one of [1] to [8] above, wherein X is -CHR ^x -; R ^x has the same meaning as in [7] above. [12] The compound or pharmacologically acceptable salt thereof of any one of [1] to [8] or [11] above, which is selected from the group consisting of the following compounds: [Chemical 8] and [Chemistry 9] [13] A pharmaceutical composition comprising a compound of any one of [1] to [12] or a pharmacologically acceptable salt thereof, and a pharmaceutical additive. [14] The pharmaceutical composition of [13] is a pharmaceutical composition for treating a thyroid-related disease. [15] The pharmaceutical composition of [14], wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.

As one embodiment, the present invention relates to a method for treating thyroid-related diseases, which includes administering a necessary amount of the pharmaceutical composition of [13] above to a patient.

As an embodiment, the present invention relates to the use of a compound of any one of [1] to [12] or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating thyroid-related diseases.

As an embodiment of the compound represented by formula (I), for example, it is a compound represented by the following formula (V); [Chemical 10] [In the formula, Ring Z is a C _6-10 aryl group, a 5- or 6-membered ring heteroaryl group, or a C _3-8 cycloalkyl group; X is -CHR ^x -, or -O-; R ^x is a hydrogen atom, Or C _1-6 alkyl; R ^V1 is a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxyl C _1-6 alkyl group, or a C _6-10 aryl group C _1-6 alkoxy; R ¹ is C _1-6 alkyl; R ² is halogen atom, cyano group, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, or Halo C _1-6 alkoxy; n is an integer from 0 to 3; when n is 2 or 3, each R ² can be the same or different from each other; R ⁴ is C _1-6 alkyl, halo C _{1- 6} alkyl, -NR ⁵ R ^{5 '} , or C _3-8 cycloalkyl; R ⁵ and R ^{5 '} are each independently a hydrogen atom, or C _1-6 alkyl]. (Compare the effectiveness of previous technologies)

The compounds of the present invention have superior TSHR antagonistic activity. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof can be used as a therapeutic agent for thyroid-related diseases.

The embodiments of the present invention will be described in more detail below.

In the present invention, unless otherwise specified, each term has the following meaning.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. "C _1-6 alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. "C _1-6 alkoxy" means a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, etc.

"Hydroxy C _1-6 alkyl" means a C _1-6 alkyl group substituted with 1 or 2 hydroxyl groups. Examples thereof include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropane-2-yl, etc. "Halogen C _1-6 alkyl" means a C _1-6 alkyl group substituted with 1 to 5 halogen atoms of the same or different types. Examples thereof include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluoropropyl, pentafluoroethyl, etc. "Halogen C _1-6 alkoxy" means a C _1-6 alkoxy group substituted with 1 to 5 halogen atoms of the same or different types. For example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy and the like can be mentioned.

"C _6-10 aryl" means phenyl or naphthyl. "5- or 6-membered ring heteroaryl" means a 5- or 6-membered ring aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms in the ring. Examples include pyridyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isothiazolyl, thiazolyl, thiazolyl, 1, 3,4-dixazolyl, 1,2,4-dixazolyl, etc. "C _3-8 cycloalkyl" means a saturated hydrocarbon group with 3 to 8 membered rings, and also includes those with partially cross-linked structures. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, and the like. "3~8 membered ring heterocycloalkyl" means a cycloalkyl group in which the carbon atoms in the ring are substituted by 1 or 2 heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms, and also includes partially cross-linked structures. . Examples include acricyclyl, tetrahydroazole, pyrrolidinyl, piperidinyl, piperidinyl, Phenyl group, sulfur Phylyl, acridine base, nitrogen bicyclo[2.2.2]octyl, 2-㗁-5-nitrobicyclo[2.2.1]heptyl, 6-㗁-3-nitrobicyclo[2.2.1]heptyl, 8-㗁-3- Azabicyclo[3.2.1]octyl, 3-㗁-8-azabicyclo[3.2.1]octyl, 2-azaspiro[3.3]heptyl, 2-㗁-6-azaspiro[3.3]heptyl, Pyrrolidone group, piperidone group, oxygen base, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

"C _6-10 aryl C _1-6 alkoxy" means a C _1-6 alkoxy group substituted by one C _6-10 aryl group. Examples include benzyloxy group.

"C _6-10 aryl C _1-6 alkyl" means a C _1-6 alkyl group substituted with one C _6-10 aryl group, for example, benzyl.

In this manual, the following abbreviations in the figures and tables have the following meanings. Boc: tert-butoxycarbonyl Boc ₂ O: di-tert-butyl dicarbonate DIPEA: N,N-diisopropylethylamine DCM: dichloromethane DMAP: 4-dimethylpyridine amino DMF: N,N-dimethylformamide DPPA: diphenylphosphoryl azide HATU: O-(7-azabenzotriazol-1-yl)-N,N,N', N'-tetramethyluronium hexafluorophosphate LDA: lithium diisopropylamide MeCN: acetonitrile MTBE: tert-butyl methyl ether NMP: N-methylpyrrolidone TEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 10% Pd/C: 10% Palladium on carbon (about 55% water-wet) 10% Pt/C: 10% platinum carbon (about 55% water wet) APS: Aminopropyl silica ODS: Octadecyl silica Method A: Column chromatography method in which a silica column is connected to the lower part of an aminopropyl silica column Ref. No.: Reference Example No. Str.: Structural formula Ex. No.: Example No. Phys. data: Physical property values IC ₅₀ : 50% inhibition concentration ¹ H-NMR: Proton nuclear magnetic resonance spectrum DMSO: Dimethyl sulfoxide DMSO-d6: Dimethyl sulfoxide-d6 CDCl ₃ : Chloroform-d1 MS: Mass analysis (The values in the table are determined by the multi-ionization method of electrospray ionization-atmospheric pressure chemical ionization method.) cAMP: adenosine 3',5'-cyclic monophosphate CHO: Chinese hamster ovary FBS: fetal bovine serum HEPES: 2-(4-(2-hydroxyethyl)-1-piperidinyl)ethanesulfonic acid IBMX: 3-isobutyl-1-methylxanthine

In the case of compounds represented by formulas (I) to (V), when there is more than one asymmetric carbon atom, the present invention also includes compounds in which each asymmetric carbon atom is in an R configuration, a compound in an S configuration, and any of the same. Combined compounds. In addition, these racemic compounds, racemic mixtures, single enantiomers and diastereomer mixtures are also included in the scope of the present invention.

Among the compounds represented by formulas (I) to (V), if cis-trans isomers exist, the present invention also includes any of the cis-trans isomers.

In the case where the compounds represented by formula (I) to (V) exist as tautomers, the present invention also includes any of the tautomers.

In the present invention, stereochemical identification can also be carried out according to methods well known in the technical field.

The compounds represented by formulas (I) to (V) can be prepared into pharmacologically acceptable salts according to conventional methods if necessary. Examples of such salts include acid addition salts and salts with a base.

Examples of acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; acid addition salts with formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and benzene sulfonate. Acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, gluten Acid addition salt of organic acids such as amino acid and aspartic acid.

Examples of the salt with an alkali include salts with an inorganic alkali such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with N-methyl-D-reduced glucosamine, N,N'-diphenylethylenediamine, TEA, piperidine, Salts of organic bases such as phenotype, pyrrolidine, arginine, lysine, and choline.

Unless otherwise specified, chemical names or structural formula suffixes related to salts such as "hydrochloride" or "HCl" are not stoichiometric descriptions, but simply refer to the salt form.

When the compounds represented by formulas (I) to (V) or their pharmacologically acceptable salts exist in crystal form, the present invention also includes any crystal form. For example, pharmacologically acceptable salts also include solvates with pharmaceutically acceptable solvents such as water or ethanol, co-crystals with an appropriate co-crystal former (Coformer), and the like.

In the compounds represented by formulas (I) to (V), part of each atom may also be replaced by the corresponding isotope. The present invention also encompasses compounds substituted with these isotopes. Examples of isotopes include ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ³⁶ Cl, ¹⁸ F, ¹²³ I, ¹²⁵ I, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, and ¹⁸ O. , and isotopes of hydrogen atoms, carbon atoms, chlorine atoms, fluorine atoms, iodine atoms, nitrogen atoms, oxygen atoms, and sulfur atoms represented by ^35S . As an embodiment, a compound in which part of the hydrogen atoms of the compounds represented by formulas (I) to (V) is replaced by ² H (D: deuterium atom) can be exemplified.

Among the compounds represented by formula (I) to (V), the compounds in which some atoms are substituted with isotopes are prepared by using commercially available building blocks into which isotopes are introduced, in the same manner as the preparation method described below. Alternatively, the compounds may be prepared by using methods described in the literature (e.g., Journal of the Society of Synthetic Organic Chemistry, Vol. 65, No. 12, pp. 1179-1190, 2007, or RADIOISOTOPES, Vol. 56, No. 11, pp. 741-750, 2007).

The compounds represented by formulas (I) to (V) of the present invention can be produced, for example, according to the methods shown in Schemes 1 to 8 or methods based thereon, or methods described in literature or methods based thereon. In Scheme, the compounds represented by formulas (I)~(V) correspond to the compounds represented by formulas (I-1)~(I-7).

The compounds represented by formula (I) to (V) of the present invention can be produced by the following methods. However, the following production methods are examples of general production methods and are not intended to limit the production methods.

In the reaction of each step, if the raw materials or reagents are commercially available, commercially available products can be used.

In the reaction of each step, the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., unless otherwise specified, it is usually 30 minutes to 3 days.

In the reaction of each step, the reaction temperature varies depending on the raw material or solvent used. Unless otherwise specified, it is usually -78°C to reflux temperature.

In the reaction of each step, the pressure varies depending on the raw material used, the solvent, the reaction temperature, etc., unless otherwise specified, it is usually 1 to 20 atmospheres.

In the reaction of each step, a microwave reactor such as the Initiator manufactured by Biotage is sometimes used. When a microwave reactor is used for the reaction, the reaction can be carried out under the following conditions: pressure range: 1~30 bar, output range: 1~400 W, reaction temperature: room temperature~300℃, reaction time: 1 minute~1 day, depending on the raw materials, solvents and machine types used.

The reaction of each step is carried out without a solvent or with an appropriate solvent unless otherwise specified. Examples of appropriate solvents include solvents that are inert to the reaction. Specific examples of the solvents used include solvents described in the reference examples or embodiments corresponding to each step, or the following solvents. Two or more of the following solvents may be mixed and used in appropriate proportions. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, cyclopentyl methyl ether, MTBE, etc.; Aromatic hydrocarbons: benzene, chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, n-hexane, n-pentane, etc.; Amides: DMF, N,N-dimethylacetamide, NMP, etc.; Halogenated hydrocarbons: DCM, 1,2-dichloroethane, carbon tetrachloride, etc.; Nitriles: MeCN, etc.; Sulfides: DMSO, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, TFA, methylsulfonic acid, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc. Ketones: acetone, methyl ethyl ketone, etc. Water.

In the reaction of each step, when a base is used, the reaction is carried out using a base suitable for the reaction. Specific examples of the base used include the bases described in the reference examples or embodiments corresponding to each step, or the following bases. Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.; Alkaline bases: sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.; Organic bases: TEA, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal epoxides: sodium ethoxide, sodium methoxide, potassium tert-butyloxide, etc.; Alkaline metal hydrides: sodium hydride, etc.; Metallic amides: sodium amide, LDA, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc. Organic magnesium: isopropyl magnesium chloride, etc. Organic lithium: methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc.

In the reaction of each step, when an acid is used, the reaction is carried out using an acid suitable for the reaction. Specific examples of the acid used include the acids described in the Reference Examples or Examples corresponding to each step, or the following acids. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, TFA, citric acid, methylsulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium (IV) chloride, etc.

In the reaction of each step, when a condensing agent is used, the reaction is carried out using a condensing agent suitable for the reaction. Specific examples of the condensation agent used include the condensation agents described in the reference examples or examples corresponding to each step, or the following condensation agents. Carbodiimides: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, etc.; Imidazole: carbonyl Diimidazole, etc.; Urea onium salts, phosphonium salts: HATU, 1H-benzotriazole-1-yloxan (dimethylamino) phosphonium hexafluorophosphate, etc.; Trioxins: 4-(4,6 -Dimethoxy-1,3,5-tris-2-yl)-4-methyl chloride Phinium, etc.; Others: propylphosphonic anhydride (cyclic trimer), etc.

In the reaction of each step, when a reducing agent is used, the reaction is carried out using a reducing agent suitable for the reaction. Specific examples of the reducing agent used include the reducing agents described in the reference examples or embodiments corresponding to each step or the following reducing agents. Metal hydrides: lithium aluminum hydride, lithium boron hydride, sodium boron hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, etc.; Boranes: BH ₃ -THF complex, picolinyl borane complex, decaborane, etc.

In the reaction of each step, when a carbonyl group introducing reagent is used, the reaction is performed using a carbonyl group introducing reagent suitable for the reaction. Specific examples of the carbonyl group introducing reagent used include, for example, the carbonyl group introducing reagents described in the reference examples or examples corresponding to each step, or the following carbonyl group introducing reagents. Phosgene: phosgene, diphosgene, triphosgene, etc.; Chloroformates: 4-nitrophenyl chloroformate, etc.; Imidazoles: carbonyldiimidazole, etc.

In each step, when a protecting group is required depending on the type of functional group, the steps may be carried out by appropriately combining the introduction and removal operations according to conventional methods. For types of protecting groups, protection, and deprotection, for example, the methods described in Peter G. M. Wuts, "Greene's Protective Groups in Organic Synthesis", fifth edition, Wiley-Interscience, 2014.

In each step, when a hydrolysis reaction is carried out, the reaction can be carried out in the presence of an acid or a base. Examples of the acid and base used include the above-mentioned examples.

In each step, when the contact reduction reaction is performed, the reaction can be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc. In addition, an acid can be used in the reaction as needed.

In each step, when a reduction reaction is performed, the reaction may be carried out in the presence of a reducing agent. Examples of the reducing agent used include those mentioned above.

In each step, when a metal reduction reaction is performed, the reaction can be carried out in the presence of a metal, etc. Examples of the metal, etc. used include iron powder, zinc powder, tin chloride, titanium trichloride, etc. In addition, an acid can be used in the reaction as necessary.

In each step, when a amide reaction is performed, the reaction can be carried out using a condensing agent in the presence or absence of a base. Examples of the condensing agent and base used include the above-mentioned examples. Moreover, when carbodiimides are used as a condensing agent, additives such as 1-hydroxybenzotriazole and DMAP may be added as necessary to carry out the reaction. In addition, this reaction can be carried out in the presence or absence of a base, or using a acyl halide group or an acid anhydride.

In each step, when a reductive amination reaction is performed, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent used include those mentioned above. In addition, the reaction can also be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst used include palladium-carbon powder, a Piermann catalyst, platinum-carbon powder, and Raney nickel.

In each step, when an aromatic nucleophilic substitution reaction is performed, the reaction may be performed in the presence of a base. Examples of the base to be used include the above-mentioned bases.

In each step, when the Negishi coupling reaction is carried out, the reaction can be carried out in the presence of an organic zinc compound, a palladium catalyst and a ligand. Examples of the palladium catalyst used include palladium acetate (II) and tris(dibenzylideneacetone)palladium (0). Examples of the ligand include Xphos, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and tris(2-methylphenyl)phosphine.

In each step, when the Suzuki-Miyaura cross-coupling reaction is performed, the reaction can be carried out in the presence of a palladium catalyst and a base. Examples of the palladium catalyst used include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) and tetrakis(triphenylphosphine)palladium(0). Examples of the base used include the above examples.

In each step, in the case of a Kurtis rearrangement reaction, the reaction can be carried out in the presence of an azide source. Examples of the azide source used include sodium azide, DPPA, and the like.

In each step, when the urea formation reaction or the urea formation reaction is carried out, the reaction can be carried out in the presence or absence of a base using a carbonyl group-introducing reagent. Examples of the carbonyl group-introducing reagent and the base used include those exemplified above.

The compound represented by formula (I-1) can be produced according to the method described in Scheme 1, for example.

[Chemistry 11] The symbols in the formula have the same meanings as above. X ¹ is a chlorine atom, a bromine atom or an iodine atom. PG ¹ is a protecting group.

Process 1-1 Compound (1-3) can also be produced by reacting compound (1-1) with compound (1-2) in the presence of a base.

Process 1-2 Compound (1-4) can also be produced by removing the protecting group of compound (1-3).

Process 1-3 Compound (I-1) can also be produced by an amide reaction of compound (1-4).

The compound represented by formula (I-2) can be produced, for example, according to the method described in Scheme 2.

[Chemistry 12] The symbols in the formula have the same meanings as above.

Process 2-1 Compound (2-1) can also be prepared by reacting compound (1-1) with DPPA and Boc ₂ O in the presence of a base.

Process 2-2 Compound (2-2) can also be produced by removing the Boc group of compound (2-1).

Process 2-3 Compound (I-2a) can also be produced by reacting compound (2-2) with trimethylsilyl isocyanate. As another method, compound (I-2) can also be produced by reacting compound (2-2) with potassium cyanate or sodium cyanate in the presence of an acid.

Process 2-4 Compound (I-2b) can also be prepared by the ureidation reaction of compound (2-2) and compound (2-3).

Process 2-5 Compound (I-2c) can also be produced by the amide reaction of compound (2-2) and compound (2-4).

The compound represented by formula (3-10) can be produced, for example, according to the method described in Scheme 3.

[Chemical 13] The symbols in the formula have the same meaning as above. PG ² is a protective group; R ^1P is a C _1-6 alkyl group, and R ^3P is a halogen atom or a C _1-6 alkyl group.

Process 3-1 Compound (3-3) can also be produced by aromatic nucleophilic substitution reaction of compound (3-1) and compound (3-2).

Process 3-2 Compound (3-4) can also be produced by metal reduction reaction of compound (3-3).

Process 3-3 Compound (3-6) can also be produced by reacting compound (3-4) with compound (3-5) in the presence of a palladium catalyst.

Process 3-4 Compound (3-7) can also be produced by contact reduction reaction of compound (3-6). As another method, compound (3-7) can be obtained by reacting compound (3-6) with sodium borohydride in the presence of cobalt (II) chloride and copper (II) sulfate, and then reacting with a base. manufacturing.

Process 3-5 Compound (3-9) can also be produced by reacting compound (3-7) with compound (3-8) in the presence of a base.

Process 3-6 Compound (3-10) can be produced by reacting compound (3-9) with a halogenating agent or alkylating agent in the presence or absence of a base. As the halogenating agent, N-fluorobenzenesulfonimide, succinimide chloride, benzenesulfonyl chloride, etc. can be used. As the alkylating agent, methyl iodide, ethyl iodide, etc. can be used.

The compound represented by formula (I-3) can be produced according to the method described in Scheme 4, for example.

[Chemical 14] The symbols in the formula have the same meaning as above. X ² is a bromine atom or an iodine atom; PG ³ is a protecting group.

Process 4-1 Compound (4-2) can also be produced by reacting compound (3-4) with compound (4-1) in the presence of a base.

Process 4-2 Compound (4-4) can also be produced by Negishi coupling reaction of compound (4-2) and compound (4-2).

Process 4-3 Compound (4-5) can also be produced by reacting compound (4-4) with an acid.

Process 4-4 Compound (I-3) can also be produced by reacting compound (4-5) with trimethylsilyl isocyanate. As another method, compound (I-3) can also be produced by reacting compound (4-5) with potassium cyanate or sodium cyanate in the presence of an acid.

The compound represented by formula (5-4) can be produced, for example, according to the method described in Scheme 5.

[Chemistry 15] The symbols in the formula have the same meanings as above. Z ^1P is a 6-membered cyclic heteroaryl group containing at least one nitrogen atom, and X ³ is a fluorine atom or a chlorine atom.

Process 5-1 Compound (5-3) can also be produced by aromatic nucleophilic substitution reaction of compound (5-1) and compound (5-2).

Process 5-2 Compound (5-4) can also be produced by reacting compound (5-3) with compound (3-8) in the presence of a base.

The compound represented by formula (I-4) can be produced, for example, according to the method described in Scheme 6.

[Chemistry 16] The symbols in the formula have the same meanings as above.

Process 6-1 Compound (6-3) can also be produced by reacting compound (6-1) with Grignard reagent (6-2).

Process 6-2 Compound (6-4) can also be produced by metal reduction reaction of compound (6-3).

Process 6-3 Compound (6-5) can also be prepared by reacting compound (6-4) with triethylsilane in the presence of an acid.

Process 6-4 Compound (6-6) can also be produced by reacting compound (6-5) with compound (4-1) in the presence of a base.

Process 6-5 Compound (6-7) can also be prepared by the Negishi coupling reaction of compound (6-6) and compound (4-3).

Process 6-6 Compound (6-8) can also be produced by reacting compound (6-7) with an acid.

Process 6-7 Compound (I-4) can also be produced by reacting compound (6-8) with trimethylsilyl isocyanate. As another method, compound (I-4) can be produced by reacting compound (6-8) with potassium cyanate, sodium cyanate, or the like in the presence of an acid.

The compound represented by formula (I-6) can be produced according to the method described in Scheme 7, for example.

[Chemical 17] The symbols in the formula have the same meaning as above. PG ⁴ is a protective group.

Process 7-1 Compound (7-2) can also be produced by aromatic nucleophilic substitution reaction of compound (7-1) and compound (3-2).

Process 7-2 Compound (7-3) can also be produced by metal reduction reaction of compound (7-2).

Process 7-3 Compound (7-4) can also be produced by reacting compound (7-3) with compound (4-1) in the presence of a base.

Process 7-4 Compound (7-5) can also be prepared by the Negishi coupling reaction of compound (7-4) and compound (4-3).

Process 7-5 Compound (7-6) can also be produced by reacting compound (7-5) with an acid.

Process 7-6 Compound (I-5) can also be produced by reacting compound (7-6) with trimethylsilyl isocyanate. As another method, compound (I-5) can be produced by reacting compound (7-6) with potassium cyanate, sodium cyanate, or the like in the presence of an acid.

Process 7-7 Compound (I-6) can also be produced by removing the protecting group of compound (I-5).

The compound represented by formula (I-7) can be produced according to the method described in Scheme 8, for example.

[Chemical 18] The symbols in the formula have the same meaning as above.

Process 8-1 Compound (8-2) can also be produced by reacting compound (8-1) with Grignard reagent (6-2).

Process 8-2 Compound (8-3) can also be produced by acidifying reaction of compound (8-2).

Process 8-3 Compound (8-5) can also be produced by reacting compound (8-3) with Grignard reagent (8-4).

Process 8-4 Compound (8-5) can also be produced by reacting compound (8-6) with Grignard reagent (6-2).

Process 8-5 Compound (8-7) can also be prepared by reacting compound (8-5) with triethylsilane in the presence of an acid.

Process 8-6 Compound (8-8) can also be produced by reacting compound (8-7) with compound (4-1) in the presence of a base.

Process 8-7 Compound (8-9) can also be prepared by the Negishi coupling reaction of compound (8-8) and compound (4-3).

Process 8-8 Compound (8-10) can also be produced by reacting compound (8-9) with an acid.

Process 8-9 Compound (8-11) can also be produced by reacting compound (8-10) with trimethylsilyl isocyanate. As another method, compound (8-11) can also be produced by reacting compound (8-10) with potassium cyanate or sodium cyanate in the presence of an acid.

Process 8-10 Compound (I-7) can also be produced by the contact reduction reaction of compound (8-11).

Each flowchart shown above is an illustration of a method for producing the compounds represented by formulas (I) to (V) or their production intermediates. Each process shown above can be variously modified into a process that can be easily understood by those with ordinary knowledge in the art.

The compounds represented by formula (I) to (V) or their intermediates can be isolated and purified by solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc., which are isolation and purification means known to those skilled in the art, as needed.

Since the compounds of the present invention have superior TSHR antagonist activity, they can be used as therapeutic agents for thyroid-related diseases. In the present invention, thyroid-related diseases include, for example, hyperthyroidism, Graves' disease, thyroid eye lesions, and thyroid cancer. The compounds of the present invention are preferably used as therapeutic agents for hyperthyroidism, Graves' disease, or thyroid eye lesions (see Endocrinology, 2014, 155 (1), p.310-314). The compounds of the present invention are more preferably used as therapeutic agents for hyperthyroidism or Graves' disease.

Furthermore, as an embodiment, hyperthyroidism includes, for example, Graves' disease, thyroiditis, toxic nodular goiter (Plummer's disease), TSH-secreting pituitary adenoma, hyperemesis gravidarum, ovarian thyroid tumor, pregnancy Hyperthyroidism caused by either trophoblastic disease or germinoma. The compound of the present invention is preferably used as a therapeutic agent for hyperthyroidism caused by Graves' disease.

Furthermore, as an embodiment, thyroid-related diseases are diseases and symptoms associated with abnormal thyroid hormone levels. Diseases and symptoms associated with abnormal thyroid hormone values include, for example, those caused by TRAb.

In the present invention, "treatment" includes the meaning of "prevention". For example, when treating hyperthyroidism, Graves' disease or thyroid eye disease, it includes the meaning of "preventing recurrence and relapse" and "maintaining remission". Furthermore, as an embodiment, the compound of the present invention can be used to treat the onset of thyroid eye disease in patients with Graves' disease.

In the present invention, "antagonist" refers to a drug that inhibits or blocks the function of a target protein regardless of its binding site. For example, "antagonist" includes "isosteric antagonist" and "negative isosteric modulator (NAM)".

The therapeutic effect of the compound of the present invention on thyroid-related diseases can be confirmed according to methods well known in the technical field. For example, as a method for confirming the effect in model animals of hyperthyroidism or Graves' disease, methods described in Endocrinology 2007, 148(5), p.2335-2344, or methods based thereon can be cited.

The pharmaceutical composition of the present invention is used in various dosage forms according to the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, eye drops, and enemas.

The pharmaceutical composition of the present invention contains the compound represented by formula (I) to (V) or a pharmacologically acceptable salt thereof as an active ingredient.

The pharmaceutical composition of the present invention is prepared using the compounds represented by formulas (I) to (V) or their pharmacologically acceptable salts, and at least one pharmaceutical additive. These pharmaceutical compositions can be combined with their dosage forms by well-known techniques in pharmaceutical preparation, and with appropriate excipients, disintegrants, binding agents, lubricants, diluents, buffers, isotonic agents, preservatives, humectants, etc. It is prepared by appropriately mixing, diluting or dissolving pharmaceutical additives such as agents, emulsifiers, dispersants, stabilizers, and dissolution auxiliaries.

When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by formula (I) to (V) or its pharmacologically acceptable salt is appropriately determined according to the patient's age, gender, weight, disease and treatment level. The daily dosage can also be divided into 1, 2, 3 or 4 times for administration. In the case of oral administration, the dosage for adults can be determined in the range of, for example, 0.1 to 5000 mg/day. As an implementation, the oral dosage can be determined in the range of 1 to 1500 mg/day, preferably in the range of 1 to 500 mg/day. In the case of parenteral administration, the dosage for adults can be determined in the range of, for example, 0.01 to 5000 mg/day. As an implementation example, the parenteral dosage can be determined in the range of 0.1~1500 mg/day, preferably in the range of 0.1~500 mg/day.

As an embodiment, the pharmaceutical composition of the present invention can also be used in combination with other drugs other than TSHR antagonists. Other drugs that can be used in combination for the treatment of thyroid-related diseases include, for example, antithyroid drugs (such as methimazole, propylthiouracil, etc.), inorganic iodine, lithium carbonate, thyroid hormone preparations, etc.

When the compound represented by formula (I) to (V) or its pharmacologically acceptable salt is used in combination with other drugs, a preparation containing these active ingredients together can be prepared, or each of these active ingredients can be prepared and administered. In the case of separate preparations, these preparations can be administered separately or simultaneously. In addition, the dosage of the compound represented by formula (I) to (V) or its pharmacologically acceptable salt can also be appropriately reduced according to the dosage of other drugs used in combination.

The compounds represented by formulas (I) to (V) can also be appropriately converted into prodrugs and used. For example, prodrugs of compounds represented by formulas (I) to (V) can be produced by using corresponding prodrug reagents such as halides to introduce the base constituting the prodrug and purifying them. Examples of bases constituting prodrugs include those described in "Development of Pharmaceuticals" (Hiroyuki Publishing House, 1990), Vol. 7, pp. 163-198. Example

The present invention will be described in further detail below based on Reference Examples, Examples and Test Examples, but the present invention is not limited to the contents.

The compound names described in the following examples are all named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc., except for commercially available reagents.

Reference example A-1 2-Bromo-6-phenoxyaniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (4.01 g), phenol (1.89 g) and DMF (40 mL), potassium carbonate (10.1 g) was added, and the mixture was stirred at 80°C for 6 hours. After the reaction mixture was cooled to room temperature, water was added. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20~50/50) to obtain 1-bromo-2-nitro-3-phenoxybenzene (5.58 g). Iron powder (3.05 g) was added to a mixture of the obtained compound (5.58 g), ethanol (43 mL) and acetic acid (43 mL), and the mixture was stirred at 91°C for 11 hours. After the reaction mixture was allowed to cool to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~94/6) to obtain the title compound (4.68 g).

Reference Example A-2 8-Phenoxy-1,2,3,4-tetrahydroquinolin-2-one A mixture of Reference Example A-1 (2.13 g), ethyl acrylate (2.42 g), palladium (II) acetate (0.181 g), tris(2-methylphenyl)phosphine (0.491 g), TEA (4.08 g) and MeCN (40 mL) was refluxed for 5 hours. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30) to obtain (2E)-3-(2-amino-3-phenoxyphenyl)prop-2-enoic acid ethyl ester (2.08 g). A mixture of the obtained compound (2.08 g), 10% Pd/C (0.400 g) and methanol (30 mL) was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was suspended in water and the insoluble matter was filtered out. The obtained solid was dried under reduced pressure to obtain the title compound (1.53 g).

Reference Example A-3 1-Methyl-8-phenoxy-1,2,3,4-tetrahydroquinolin-2-one Sodium hydroxide (about 60%) (0.022 g) was added to a mixture of Reference Example A-2 (0.100 g), methyl iodide (0.119 g) and THF (2 mL) under ice-cooling, and stirred at room temperature for 1 hour. Ice water was added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 74/26~57/43) to obtain the title compound (0.102 g).

Reference example A-4 2-Bromo-6-(2-fluorophenoxy)aniline To the mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.00 g), 2-fluorophenol (0.561 g) and DMF (10 mL), add potassium carbonate (1.57 g) and stir at 100°C for 1 hours. After the reaction mixture was cooled to room temperature, water was added and stirred at room temperature for 15 minutes. The insoluble matter was filtered off, and the obtained solid was dissolved in ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Iron powder (0.762 g) was added to the mixture of the residue, ethanol (12 mL) and acetic acid (12 mL), and the mixture was stirred at 90°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate aqueous solution were added to the residue, and the mixture was filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (1.32 g).

Reference example A-5 8-(2-fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Reference example A-4 (1.23 g), benzyl acrylate (1.41 g), palladium (II) acetate (0.098 g), ginseng (2-methylphenyl)phosphine (0.265 g), TEA (1.77 g) and The mixture of MeCN (10 mL) was stirred at 135°C for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10~40/60) to obtain 3-(2-amino-3-(2-fluorophenoxy) )phenyl)prop-2-enoic acid benzyl ester (1.12 g). A mixture of the obtained compound (1.12 g), 10% Pd/C (0.100 g) and DMF (10 mL) was stirred at 60°C for 1 hour in a hydrogen environment. The reaction mixture was stirred at 80°C for 1 hour under hydrogen atmosphere. Ethanol (10 mL) was added to the reaction mixture, and the mixture was stirred at 70°C for 1 hour in a hydrogen environment. After the reaction mixture was allowed to cool to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue, 10% Pd/C (0.100 g) and acetic acid (10 mL) was stirred at 80°C for 2 hours in a hydrogen environment. Concentrated sulfuric acid (0.020 mL) was added to the reaction mixture, and the mixture was stirred at 80°C for 2 hours in a hydrogen environment. After the reaction mixture was allowed to cool to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 67/33~37/63) to obtain 8-(2-fluorophenoxy)-1,2,3,4 -Tetrahydroquinolin-2-one (0.638 g). To a mixture of the obtained compound (0.638 g) and DMF (10 mL), sodium hydride (about 60%) (0.119 g) and methane iodide (0.704 g) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water and diethyl ether were added to the reaction mixture under ice-cooling. The mixture was extracted with diethyl ether. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 83/17~18/82) to obtain the title compound (0.672 g).

Reference Example A-6 2-Bromo-6-(3-fluorophenoxy)aniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.500 g), 3-fluorophenol (0.255 g) and DMF (5 mL), potassium carbonate (0.471 g) was added and stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, water and diethyl ether were added. The mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Iron powder (0.381 g) was added to a mixture of residue, ethanol (6 mL) and acetic acid (6 mL), and stirred at 90°C for 1 hour. After the reaction mixture was cooled to room temperature, it was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate aqueous solution were added to the residue and the mixture was filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (0.681 g).

Reference example A-7 8-(3-fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Reference example A-6 (0.641 g), benzyl acrylate (0.737 g), palladium (II) acetate (0.051 g), ginseng (2-methylphenyl)phosphine (0.138 g), TEA (0.920 g) and The mixture of MeCN (10 mL) was stirred at 130°C for 1 hour under microwave irradiation. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10~59/41) to obtain 3-(2-amino-3-(3-fluorophenoxy) )phenyl)prop-2-enoic acid benzyl ester (0.382 g). A mixture of the obtained compound (0.382 g), 10% Pd/C (0.040 g) and acetic acid (5 mL) was stirred at 80°C for 2 hours in a hydrogen environment. After the reaction mixture was cooled to room temperature, it was filtered through celite. The mixture of the filtrate and 10% Pd/C (0.040 g) was stirred at 80°C for 1 hour in a hydrogen environment, and then stirred at 100°C for 3 hours. After the reaction mixture was allowed to cool to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 67/33~24/76) to obtain 8-(3-fluorophenoxy)-1,2,3,4 -Tetrahydroquinolin-2-one (0.135 g). Sodium hydride (approximately 60%) (0.025 g) was added to a mixture of the obtained compound (0.135 g), methane iodide (0.149 g) and DMF (2 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water and diethyl ether were added to the reaction mixture under ice-cooling. The mixture was extracted with diethyl ether. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10~31/69) to obtain the title compound (0.156 g).

Reference example A-8 Reference Example A-8 was synthesized by using 3-(trifluoromethyl)phenol instead of 3-fluorophenol in the same manner as Reference Example A-6.

Reference example A-9 1-Methyl-8-(3-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-2-one Reference example A-8 (1.27 g), benzyl acrylate (1.24 g), palladium (II) acetate (0.086 g), ginseng (2-methylphenyl)phosphine (0.233 g), TEA (1.55 g) and The mixture of MeCN (10 mL) was stirred at 130°C for 1 hour under microwave irradiation. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~50/50) to obtain 3-(2-amino-3-(3-(trifluoromethyl) Benzyl)phenoxy)phenyl)prop-2-enoate (1.48 g). A mixture of the obtained compound (1.48 g), 10% Pd/C (0.382 g) and acetic acid (18 mL) was stirred at 80°C for 6 hours in a hydrogen environment. After the reaction mixture was cooled to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 60/40~33/67) to obtain 8-(3-(trifluoromethyl)phenoxy)-1, 2,3,4-Tetrahydroquinolin-2-one (0.661 g). Sodium hydride (approximately 60%) (0.086 g) was added to a mixture of the obtained compound (0.661 g), methane iodide (0.305 g) and DMF (5 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water and diethyl ether were added to the reaction mixture under ice-cooling. The mixture was extracted with diethyl ether. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20~38/62) to obtain the title compound (0.607 g).

Reference example A-10 2-Bromo-6-(3-chlorophenoxy)aniline To the mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.746 g), 3-chlorophenol (0.436 g) and DMF (10 mL), add potassium carbonate (0.937 g) and stir at 100°C for 1 hours. After the reaction mixture was cooled to room temperature, water and diethyl ether were added. The mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Iron powder (0.947 g) was added to the mixture of the residue, ethanol (12 mL) and acetic acid (12 mL), and the mixture was stirred at 90°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. To the mixture of the residue and ethyl acetate, 2 mol/L sodium hydroxide aqueous solution was added under ice cooling. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (0.963 g).

Reference Example A-11 8-(3-Chlorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one A mixture of Reference Example A-10 (0.963 g), benzyl acrylate (1.05 g), palladium (II) acetate (0.072 g), tris(2-methylphenyl)phosphine (0.196 g), TEA (1.80 g) and MeCN (10 mL) was stirred at 130°C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~0/100) to obtain 3-(2-amino-3-(3-chlorophenoxy)phenyl)prop-2-enoic acid benzyl ester (0.955 g). To a mixture of the obtained compound (0.955 g), methanol (5 mL) and THF (5 mL) were added cobalt chloride (II) pentahydrate (0.002 g), copper (II) sulfate (0.012 g) and sodium borohydride (0.105 g) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and then a 2 mol/L sodium hydroxide aqueous solution (3.77 mL) was added and stirred at 50°C for 30 minutes. The reaction mixture was cooled to room temperature, and then 2 mol/L hydrochloric acid (3.77 mL) was added. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Methyl iodide (0.693 g) and sodium hydroxide (about 60%) (0.107 g) were added to the mixture of the residue and DMF (10 mL) at room temperature and stirred at room temperature for 30 minutes. Water was added to the reaction mixture under ice cooling and extracted with diethyl ether. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10~0/100) to obtain the title compound (0.345 g).

Reference Example A-12 Reference Example A-12 was synthesized by the same method as Reference Example A-10, using 1-bromo-3,4-difluoro-2-nitrobenzene instead of 1-bromo-3-fluoro-2-nitrobenzene and using phenol instead of 3-chlorophenol.

Reference example A-13 7-Fluoro-1-methyl-8-phenoxy-1,2,3,4-tetrahydroquinolin-2-one Reference example A-12 (1.20 g), benzyl acrylate (1.38 g), palladium (II) acetate (0.095 g), ginseng (2-methylphenyl)phosphine (0.259 g), TEA (2.15 g) and The mixture of MeCN (10 mL) was stirred at 130°C for 1 hour under microwave irradiation. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 92/8~43/57) to obtain 3-(2-amino-4-fluoro-3-phenoxy) Benzyl phenyl)prop-2-enoate (1.03 g). To a mixture of the obtained compound (0.998 g), methanol (7 mL) and THF (7 mL), cobalt (II) chloride pentahydrate (0.002 g), copper (II) sulfate (0.013 g) and Sodium borohydride (0.229 g). After the reaction mixture was stirred at room temperature for 10 minutes, 2 mol/L hydrochloric acid (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 10 minutes. 2 mol/L sodium hydroxide aqueous solution (0.5 mL) and DCM were added to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes and at 50°C for 30 minutes. Concentrated hydrochloric acid (1 mL) was added to the reaction mixture at room temperature and stirred for 10 minutes. Ethyl acetate and water were added to the mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 65/35~26/74) to obtain 7-fluoro-8-phenoxy-1,2,3,4- Tetrahydroquinolin-2-one (0.554 g). Sodium hydride (approximately 60%) (0.103 g) was added to a mixture of the obtained compound (0.554 g), methane iodide (0.458 g) and DMF (6 mL), and the mixture was stirred at room temperature for 30 minutes. Water and diethyl ether were added to the reaction mixture under ice-cooling. The mixture was extracted with diethyl ether, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30~35/65) to obtain the title compound (0.606 g).

Reference Example A-14 Reference Example A-14 was synthesized by the same method as Reference Example A-10, using 1-chloro-2-fluoro-3-nitrobenzene instead of 1-bromo-3-fluoro-2-nitrobenzene and using phenol instead of 3-chlorophenol.

Reference Example A-15 7-Chloro-1-methyl-8-phenoxy-1,2,3,4-tetrahydroquinolin-2-one Pyridine (0.630 g) and 9-fluorenylmethyl chloroformate (1.65 g) were added to the mixture of Reference Example A-14 (1.17 g) and DCM (20 mL) under ice-cooling, and stirred at room temperature for 30 minutes. 1 mol/L hydrochloric acid was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~44/56) to obtain N (3-chloro-2-phenoxyphenyl) carbamic acid (9H-fluoren-9-yl) methyl ester (1.01 g). A mixture of the obtained compound (1.01 g), n-butyl acrylate (0.589 g), potassium (II) acetate (0.052 g), potassium persulfate (0.683 g), TFA (16 mL) and DCM (4 mL) was stirred at room temperature for 14 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to a mixture of the residue and ethyl acetate under ice cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~43/57) to obtain butyl 3-(4-chloro-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-phenoxyphenyl)prop-2-enoate (0.271 g). Piperidine (0.203 g) was added to a mixture of the obtained compound (0.271 g) and DCM (2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~68/32) to obtain butyl 3-(2-amino-4-chloro-3-phenoxyphenyl)prop-2-enoate (0.196 g). To a mixture of the obtained compound (0.196 g), methanol (5 mL) and THF (5 mL), cobalt chloride (II) pentahydrate (0.374 mg), copper (II) sulfate (2.71 mg) and sodium borohydride (0.024 g) were added, and stirred at room temperature for 10 minutes. A 2 mol/L sodium hydroxide aqueous solution (0.850 mL) was added to the reaction mixture, and stirred at 50°C for 30 minutes. After the mixture was cooled to room temperature, acetic acid (0.170 g) was added and the mixture was concentrated under reduced pressure. Acetic acid (2 mL) was added to the residue, and after stirring at 50°C for 30 minutes, the mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the mixture of the residue and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30~37/63) to obtain 7-chloro-8-phenoxy-1,2,3,4-tetrahydroquinolin-2-one (0.060 g). To the mixture of the obtained compound (0.060 g) and DMF (1 mL), iodomethane (0.047 g) and sodium hydroxide (about 60%) (0.011 g) were added under ice-cooling and stirred at room temperature for 30 minutes. Water and diethyl ether were added to the reaction mixture under ice-cooling. The mixture was extracted with diethyl ether, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5~32/68) to obtain the title compound (0.061 g).

Reference Example A-16 1-Methyl-8-((3-(trifluoromethyl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinolin-2-one To a mixture of 8-hydroxy-1,2,3,4-tetrahydroquinolin-2-one (0.200 g), NMP (5 mL) and 2-chloro-3-(trifluoromethyl)pyridine (0.289 g), potassium carbonate (0.508 g) was added and stirred at 110°C for 8 hours. After the reaction mixture was cooled to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 60/40~0/100) to obtain 8-((3-(trifluoromethyl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinolin-2-one (0.240 g). Sodium hydroxide (about 60%) (0.047 g) was added to a mixture of the obtained compound (0.240 g), DMF (2 mL) and methyl iodide (0.166 g) under ice-cooling, and stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution, ethyl acetate and n-hexane were added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10~60/40) to obtain the title compound (0.240 g).

Reference Example B-1 2-Bromo-N-methyl-6-(2-(trifluoromethyl)phenoxy)aniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.00 g), 2-(trifluoromethyl)phenol (0.737 g) and NMP (10 mL), potassium carbonate (1.26 g) was added and stirred at 110°C for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of residue, ethanol (15 mL) and water (5 mL), ammonium chloride (6.08 g) and iron powder (1.27 g) were added and stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~80/20) to obtain 2-bromo-6-(2-(trifluoromethyl)phenoxy)aniline (1.50 g). Methyl lithium (1.12 mol/L in diethyl ether) (0.887 mL) was added to the mixture of the obtained compound (0.300 g) and THF (3 mL) at -78°C and stirred at the same temperature for 1 hour. After adding a mixture of iodomethane (0.154 g) and THF (2 mL) to the reaction mixture at -78°C, stir at the same temperature for 10 minutes and stir under ice-cooling for 2 hours. Add a saturated aqueous ammonium chloride solution to the reaction mixture under ice-cooling. Extract the mixture with ethyl acetate and wash the extract with saturated brine. Dry the extract over anhydrous sodium sulfate and concentrate under reduced pressure. Purify the residue by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~80/20) to obtain the title compound (0.250 g).

Reference Example B-2 (3R)-3-amino-1-methyl-8-(2-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-2-one Zinc (0.104 g) was added to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.285 g) and DMF (4 mL), and the mixture was stirred at room temperature for 2 hours. Reference Example B-1 (0.250 g), palladium (II) acetate (0.008 g), and Xphos (0.034 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 13 hours. Saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate. The extract was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. TFA (1.65 g) was added to the mixture of the residue and DCM (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. A 5 mol/L aqueous sodium hydroxide solution (3 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2~0/98/2~0/86/14) to obtain the title compound (0.084 g).

Reference Example B-3 2-Bromo-6-(2-methoxyphenoxy)-N-methylaniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.612 g), 2-methoxyphenol (0.345 g) and DMF (10 mL), potassium carbonate (0.769 g) was added and stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, water and diethyl ether were added. The mixture was extracted with diethyl ether and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Iron powder (0.777 g) was added to a mixture of residue, ethanol (6 mL) and acetic acid (3 mL) and stirred at 90°C for 1 hour. After the reaction mixture was cooled to room temperature, it was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. To the mixture of the residue and ethyl acetate, a 2 mol/L aqueous sodium hydroxide solution was added under ice cooling. The mixture was filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the mixture of the residue and THF (10 mL), methyl lithium (1.06 mol/L in diethyl ether) (2.72 mL) was added at -78°C and stirred at the same temperature for 30 minutes. After adding a mixture of iodomethane (0.375 g) and THF (1 mL) to the reaction mixture at -78°C, stir at the same temperature for 10 minutes and stir under ice cooling for 30 minutes. Add a saturated aqueous ammonium chloride solution to the reaction mixture under ice cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~55/45) to obtain the title compound (0.544 g).

Reference example B-4 (3R)-3-Amino-8-(2-methoxyphenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to the mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.384 g) and DMF (5 mL), zinc (0.140 g ) and stir at room temperature for 2 hours. Reference Example B-3 (0.300 g), palladium (II) acetate (0.011 g), and Xphos (0.046 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and ethyl acetate. The mixture was filtered through celite. The filtrate was extracted with ethyl acetate. Wash the extract with water. After drying over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol/L in 1,4-dioxane) (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the mixture of the residue and ethyl acetate was added saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=50/50/0~0/100/0~0/50/50) to obtain the title compound (0.173 g) .

Reference example B-5 3-(3-Bromo-2-(methylamino)phenoxy)benzonitrile To the mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.01 g), 3-hydroxybenzonitrile (0.548 g) and DMF (10 mL), add potassium carbonate (1.27 g) and stir at 100°C. 1 hour. After the reaction mixture was cooled to room temperature, water was added. The insoluble matter was filtered off, and the obtained solid was washed with DMF/water (1/2) and water, and dried under reduced pressure to obtain 3-(3-bromo-2-nitrophenoxy)benzonitrile (1.33 g). Ammonium chloride (5.57 g) and iron powder (1.16 g) were added to a mixture of the obtained compound (1.33 g), ethanol (15 mL) and water (5 mL), and the mixture was stirred at 80°C for 1 hour. After the reaction mixture was cooled to room temperature, it was filtered through celite. After adding water to the filtrate, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure to obtain 3-(2-amino-3-bromophenoxy)benzonitrile (1.22 g). Under an argon environment, add methyllithium (1.06 mol/L in diethyl ether) (4.2 mL) to a mixture of the obtained compound (1.17 g) and THF (12 mL) at -78°C, and stir at the same temperature. Stir for 1 hour. A mixture of methane iodide (0.687 g) and THF (7 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes, and then stirred under ice-cooling for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~85/15) to obtain the title compound (1.24 g).

Reference example B-6 3-(((3R)-3-Amino-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-8-yl)oxy)benzonitrile Under an argon environment, to the mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (1.44 g) and DMF (8 mL), zinc (0.527 g ) and stir at room temperature for 2 hours. A mixture of Reference Example B-5 (1.11 g) and DMF (3 mL), palladium (II) acetate (0.042 g), and Xphos (0.174 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 13 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and ethyl acetate. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. Wash the extract with water. After drying over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. To a mixture of the residue and DCM (11 mL), TFA (8.33 g) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A 5 mol/L sodium hydroxide aqueous solution (13.2 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=50/50/0~0/100/0~0/85/15) to obtain the title compound (0.570 g) .

Reference Example B-7 Reference Example B-7 was synthesized by the same method as Reference Example B-3, using 3-methoxyphenol instead of 2-methoxyphenol.

Reference example B-8 (3R)-3-Amino-8-(3-methoxyphenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to the mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.432 g) and DMF (5 mL), zinc (0.143 g ) and stir at room temperature for 1 hour. A mixture of Reference Example B-7 (0.270 g) and DMF (0.5 mL), palladium (II) acetate (0.010 g), and Xphos (0.042 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and diethyl ether. The mixture was filtered through celite, and the filtrate was extracted with diethyl ether. Wash the extract with water. After drying over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol/L in 1,4-dioxane) (3 mL) was stirred under ice-cooling for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the mixture of the residue and ethyl acetate was added saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=30/70/0~0/100/0~0/70/30) to obtain the title compound (0.167 g) .

Reference Example B-9 Reference Example B-9 was synthesized by the same method as Reference Example B-3, using 2-ethylphenol instead of 2-methoxyphenol.

Reference Example B-10 Reference Example B-9 was used instead of Reference Example B-7, and Reference Example B-10 was synthesized by the same method as Reference Example B-8.

Reference example B-11 Reference Example B-11 was synthesized by the same method as Reference Example B-3 except that 3-ethylphenol was used instead of 2-methoxyphenol.

Reference Example B-12 (3R)-3-amino-8-(3-ethylphenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Zinc (0.143 g) was added to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.432 g) and DMF (5 mL) in an hydrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. A mixture of Reference Example B-11 (0.268 g) and DMF (1 mL), palladium (II) acetate (0.010 g), and Xphos (0.042 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol/L in 1,4-dioxane) (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to a mixture of the residue and ethyl acetate. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 30/70/0~0/100/0~0/70/30) to obtain the title compound (0.110 g).

Reference Example B-13 2-Bromo-6-(2-chloro-5-fluorophenoxy)-N-methylaniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.300 g), 2-chloro-5-fluorophenol (0.220 g) and DMF (10 mL), potassium carbonate (0.377 g) was added and stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, water and diethyl ether were added. The mixture was extracted with diethyl ether and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, ethanol (9 mL) and water (3 mL), ammonium chloride (1.46 g) and iron powder (0.777 g) were added and stirred at 90°C for 1 hour. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~75/25) to obtain 2-bromo-6-(2-chloro-5-fluorophenoxy)aniline (0.417 g). Methyl lithium (1.06 mol/L in diethyl ether) (1.37 mL) was added to the mixture of the obtained compound (0.417 g) and THF (7 mL) at -78°C and stirred at the same temperature for 30 minutes. After adding iodomethane (0.224 g) to the reaction mixture at -78°C, stir at the same temperature for 10 minutes and stir under ice cooling for 30 minutes. Add saturated aqueous ammonium chloride solution to the reaction mixture under ice cooling. After the mixture was extracted with ethyl acetate, the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~77/23) to obtain the title compound (0.436 g).

Reference Example B-14 (3R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Zinc (0.215 g) was added to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.650 g) and DMF (7 mL) in an hydrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. A mixture of Reference Example B-13 (0.435 g) and DMF (1 mL), palladium (II) acetate (0.015 g), and Xphos (0.063 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol/L in 1,4-dioxane) (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to a mixture of the residue and ethyl acetate. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 30/70/0~0/100/0~0/71/29) to obtain the title compound (0.198 g).

Reference Example B-15 2-Bromo-N-methyl-6-(2-isopropylphenoxy)aniline Potassium carbonate (0.648 g) was added to a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.516 g), 2-isopropylphenol (0.351 g) and DMF (5 mL), and stirred at 100°C for 1 hour. Water and toluene were added to the reaction mixture under water cooling. The mixture was extracted with toluene, and the extract was washed with water. The extract was concentrated under reduced pressure to obtain 1-bromo-3-(2-isopropylphenoxy)-2-nitrobenzene (1.01 g). To a mixture of the obtained compound (0.774 g), ethanol (8 mL) and water (2.7 mL), ammonium chloride (3.00 g) and iron powder (0.638 g) were added and stirred at 80°C for 2 hours. The reaction mixture was cooled with water and filtered through diatomaceous earth. Water was added to the filtrate and then extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30) to obtain 2-bromo-6-(2-isopropylphenoxy)aniline (0.746 g). To the mixture of the obtained compound (0.672 g) and THF (7 mL), methyl lithium (1.04 mol/L in diethyl ether) (2.5 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a mixture of iodinated methyl (0.374 g) and THF (4 mL) was added at -78°C, and the mixture was stirred under water cooling for 1 hour. To the reaction mixture, a saturated aqueous ammonium chloride solution and water were added under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~90/10) to obtain the title compound (0.787 g).

Reference example B-16 (3R)-3-Amino-1-methyl-8-(2-isopropylphenoxy)-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.312 g) was added to a mixture of Reference Example B-15 (0.685 g) and DMF (6 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.845 g), palladium (II) acetate (0.026 g), and Xphos (0.104 g) ) and stir at room temperature for 14 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution, water and ethyl acetate. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was concentrated under reduced pressure. Ethyl acetate, water and toluene were added to the residue. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue and DCM (7 mL), TFA (4.88 g) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. A 5 mol/L sodium hydroxide aqueous solution (8.5 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the organic layer was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=50/50/0~0/100/0~0/80/20) to obtain the title compound (0.357 g) .

Reference Example B-17 2-Bromo-6-(2-(difluoromethyl)phenoxy)-N-methylaniline Add potassium carbonate (0.660 g) to a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.522 g), 2-hydroxybenzaldehyde (0.290 g) and DMF (5 mL), and stir at 100°C for 1 hour. After cooling the reaction mixture to room temperature, add water, ethyl acetate and toluene. Add saturated ammonium chloride aqueous solution and 2 mol/L hydrochloric acid to the mixture. Extract the mixture with ethyl acetate and wash the extract with water. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~55/45) to obtain 2-(3-bromo-2-nitrophenoxy)benzaldehyde (0.686 g). Bis(2-methoxyethyl)aminosulfur trifluoride (0.937 g) was added to a mixture of the obtained compound (0.682 g), DCM (3.4 mL) and ethanol (0.020 g), and stirred at 50°C for 2 hours. An ice-cold saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~50/50) to obtain 1-bromo-3-(2-(difluoromethyl)phenoxy)2-nitrobenzene (0.674 g). Ammonium chloride (2.30 g) and iron powder (0.480 g) were added to a mixture of the obtained compound (0.588 g), ethanol (6 mL) and water (2 mL), and stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30) to obtain 2-bromo-6-(2-(difluoromethyl)phenoxy)aniline (0.488 g). Methyl lithium (1.04 mol/L in diethyl ether) (1.6 mL) was added to a mixture of the obtained compound (0.482 g) and THF (5 mL) at -78°C, and stirred at the same temperature for 1 hour. A mixture of iodinated methyl (0.261 g) and THF (3 mL) was added to the reaction mixture at -78°C, and stirred under ice-cooling for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~90/10) to obtain the title compound (0.555 g).

Reference example B-18 Reference Example B-17 was used instead of Reference Example B-15, and Reference Example B-18 was synthesized by the same method as Reference Example B-16.

Reference example B-19 Instead of 1-bromo-3-fluoro-2-nitrobenzene, use 1-bromo-3,4-difluoro-2-nitrobenzene, replace 2-chloro-5-fluorophenol and use 2-chlorophenol, borrow Reference Example B-19 was synthesized by the same method as Reference Example B-13.

Reference example B-20 Reference Example B-19 was used instead of Reference Example B-11, and Reference Example B-20 was synthesized by the same method as Reference Example B-12.

Reference Example B-21 Reference Example B-21 was synthesized by the same method as Reference Example B-13, using 2-chloro-4-fluorophenol instead of 2-chloro-5-fluorophenol.

Reference example B-22 (3R)-3-Amino-8-(2-chloro-4-fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to the mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.659 g) and DMF (7 mL), zinc (0.218 g ) and stir at room temperature for 1 hour. A mixture of Reference Example B-21 (0.441 g) and DMF (1 mL), palladium (II) acetate (0.015 g), and Xphos (0.064 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and ethyl acetate. The mixture was extracted with ethyl acetate, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue and DCM (7 mL), TFA (3.04 g) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. 5 mol/L sodium hydroxide aqueous solution (1.8 mL) was added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=40/60/0~0/100/0~0/35/65) to obtain the title compound (0.295 g) .

Reference Example B-23 2-Bromo-6-(5-fluoro-2-(trifluoromethyl)phenoxy)-N-methylaniline Add potassium carbonate (0.188 g) to a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.150 g), 5-fluoro-2-(trifluoromethyl)phenol (0.135 g) and NMP (2 mL), and stir at 110°C for 6 hours. After cooling the reaction mixture to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the mixture of the residue, ethanol (3 mL) and water (1 mL), ammonium chloride (0.912 g) and iron powder (0.190 g) were added, and the mixture was stirred at 80°C for 2 hours. After the reaction mixture was cooled to room temperature, water was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 2-bromo-6-(5-fluoro-2-(trifluoromethyl)phenoxy)aniline (0.120 g). To the mixture of the obtained compound (0.120 g) and THF (1 mL), methyl lithium (1.06 mol/L in diethyl ether) (0.356 mL) was added at -78°C, and stirred at the same temperature for 1 hour. After adding a mixture of iodomethane (0.058 g) and THF (1 mL) to the reaction mixture at -78°C, stir at the same temperature for 10 minutes and stir under ice cooling for 1 hour. Add a saturated aqueous ammonium chloride solution to the reaction mixture under ice cooling. Extract the mixture with DCM, and concentrate the extract under reduced pressure. Purify the residue by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.094 g).

Reference example B-24 Reference Example B-23 was used instead of Reference Example B-1, and Reference Example B-24 was synthesized by the same method as Reference Example B-2.

Reference example B-25 6-Bromo-3-chloro-2-(2-chlorophenoxy)-N-methylaniline To the mixture of 1-bromo-4-chloro-3-fluoro-2-nitrobenzene (0.150 g), 2-chlorophenol (0.076 g) and NMP (2 mL), add potassium carbonate (0.188 g) and mix at 110 °C and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ammonium chloride (0.788 g) and iron powder (0.165 g) were added to a mixture of the residue, ethanol (3 mL) and water (1 mL), and the mixture was stirred at 80°C for 1.5 hours. After the reaction mixture was allowed to cool to room temperature, water was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 6-bromo-3-chloro-2-(2-chlorophenoxy)aniline (0.110 g). To a mixture of the obtained compound (0.110 g) and THF (1 mL), methyllithium (1.06 mol/L in diethyl ether) (0.343 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. A mixture of methane iodide (0.056 g) and THF (1 mL) was added to the reaction mixture at -78°C, followed by stirring at the same temperature for 10 minutes and at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.100 g).

Reference example B-26 Reference Example B-25 was used instead of Reference Example B-1, and Reference Example B-26 was synthesized by the same method as Reference Example B-2.

Reference example B-27 Reference Example B-27 was synthesized by the same method as Reference Example B-25, except that 2-fluorophenol was used instead of 2-chlorophenol.

Reference example B-28 Reference Example B-27 was used instead of Reference Example B-1, and Reference Example B-28 was synthesized by the same method as Reference Example B-2.

Reference example B-29 2-Bromo-6-(3-(difluoromethoxy)phenoxy)-N-methylaniline To a mixture of 3-(benzyloxy)phenol (1.01 g) and MeCN (25 mL) was added a mixture of potassium hydroxide (5.62 g) and water (25 mL) at room temperature. Diethyl (bromodifluoromethyl)phosphonate (2.69 g) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was washed with water and concentrated under reduced pressure. Ethanol (10 mL) and 10% Pd/C (0.204 g) were added to the residue, and the mixture was stirred at room temperature under a hydrogen atmosphere for 13 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure. Potassium carbonate (0.794 g) was added to a mixture of the residue, 1-bromo-3-fluoro-2-nitrobenzene (0.630 g) and DMF (6 mL), and the mixture was stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, water, ethyl acetate and toluene were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30) to obtain 1-bromo-3-(3-(difluoromethoxy)phenoxy) (0.871 g). Ammonium chloride (3.21 g) and iron powder (0.671 g) were added to a mixture of the obtained compound (0.866 g), ethanol (9 mL) and water (3 mL), and the mixture was stirred at 80°C for 2.5 hours. After the reaction mixture was water-cooled, it was filtered through diatomaceous earth. After adding water to the filtrate, the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~50/50) to obtain 2-bromo-6-(3-(difluoromethoxy)phenoxy) base)aniline (0.758 g). To a mixture of the obtained compound (0.751 g) and THF (8 mL), methyllithium (1.04 mol/L in diethyl ether) (2.6 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. A mixture of methane iodide (0.387 g) and THF (5 mL) was added to the reaction mixture at -78°C, and the mixture was stirred under water cooling for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under water cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~90/10) to obtain the title compound (0.687 g).

Reference Example B-30 Reference Example B-29 was used instead of Reference Example B-1, and Reference Example B-30 was synthesized by the same method as Reference Example B-2.

Reference example B-31 Use 1-bromo-4-chloro-3-fluoro-2-nitrobenzene instead of 1-bromo-3-fluoro-2-nitrobenzene, and use it instead of 5-fluoro-2-(trifluoromethyl)phenol 3-Methoxyphenol was synthesized in Reference Example B-31 by the same method as Reference Example B-23.

Reference Example B-32 Reference Example B-31 was used instead of Reference Example B-1, and Reference Example B-32 was synthesized by the same method as Reference Example B-2.

Reference example B-33 Use 1-bromo-4-chloro-3-fluoro-2-nitrobenzene instead of 1-bromo-3-fluoro-2-nitrobenzene, and use it instead of 5-fluoro-2-(trifluoromethyl)phenol 3-Fluorophenol was synthesized in Reference Example B-33 by the same method as Reference Example B-23.

Reference Example B-34 Reference Example B-33 was used instead of Reference Example B-1, and Reference Example B-34 was synthesized by the same method as Reference Example B-2.

Reference Example B-35 6-Bromo-3-chloro-2-(2-(difluoromethyl)phenoxy)-N-methylaniline To a mixture of 1-bromo-4-chloro-3-fluoro-2-nitrobenzene (0.200 g), 2-hydroxybenzaldehyde (0.096 g) and NMP (2 mL), potassium carbonate (0.217 g) was added and stirred at 110°C for 3 hours. After the reaction mixture was cooled to room temperature, 1 mol/L hydrochloric acid, ethyl acetate and n-hexane were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~80/20) to obtain 2-(3-bromo-6-chloro-2-nitrophenoxy)benzaldehyde (0.160 g). Bis(2-methoxyethyl)aminosulfur trifluoride (0.199 g) was added to the mixture of the obtained compound (0.160 g) and DCM (3 mL) under ice-cooling, and stirred at 50°C for 2 hours. Bis(2-methoxyethyl)aminosulfur trifluoride (0.496 g) was added to the reaction mixture, and stirred at 50°C for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 1-bromo-4-chloro-3-(2-(difluoromethyl)phenoxy)-2-nitrobenzene (0.130 g). To a mixture of the obtained compound (0.130 g), ethanol (3 mL) and water (1 mL) were added ammonium chloride (0.459 g) and iron powder (0.096 g), and stirred at 80°C for 2 hours. After the reaction mixture was cooled to room temperature, water was added. The mixture was extracted with DCM, the extract was concentrated under reduced pressure, and the residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 6-bromo-3-chloro-2-(2-(difluoromethyl)phenoxy)aniline (0.110 g). Methyl lithium (1.06 mol/L in diethyl ether) (0.327 mL) was added to the mixture of the obtained compound (0.110 g) and THF (1 mL) at -78°C, and stirred at the same temperature for 1 hour. A mixture of iodinated methyl (0.054 g) and THF (1 mL) was added to the reaction mixture at -78°C, stirred at the same temperature for 10 minutes, and stirred under ice-cooling for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.085 g).

Reference Example B-36 Reference Example B-35 was used instead of Reference Example B-1, and Reference Example B-36 was synthesized by the same method as Reference Example B-2.

Reference Example B-37 2-Bromo-6-(2-(difluoromethyl)-5-fluorophenoxy)-N-methylaniline Potassium carbonate (1.30 g) was added to a mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.04 g), 4-fluoro-2-hydroxybenzaldehyde (0.701 g) and DMF (10 mL), and stirred at 100°C for 4 hours. After the reaction mixture was cooled to room temperature, water, ethyl acetate and MTBE were added. After the mixture was extracted with ethyl acetate, the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~60/40) to obtain 2-(3-bromo-2-nitrophenoxy)-4-fluorobenzaldehyde (0.455 g). To a mixture of the obtained compound (0.361 g), DCM (4 mL) and ethanol (0.012 g) was added bis(2-methoxyethyl)aminosulfur trifluoride (0.587 g), and stirred at 50°C for 2.5 hours. The reaction mixture was added to an ice-cooled 5 mol/L aqueous sodium hydroxide solution. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~50/50) to obtain 1-bromo-3-(2-(difluoromethyl)-5-fluorophenoxy)-2-nitrobenzene (0.359 g). To a mixture of the obtained compound (0.286 g), ethanol (3 mL) and water (1 mL), ammonium chloride (1.06 g) and iron powder (0.223 g) were added and stirred at 80°C for 1 hour. The reaction mixture was cooled with water and filtered through diatomaceous earth. After adding water to the filtrate, the mixture was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~60/40) to obtain 2-bromo-6-(2-(difluoromethyl)-5-fluorophenoxy)aniline (0.256 g). To a mixture of the obtained compound (0.247 g) and THF (3 mL), methyl lithium (1.04 mol/L in diethyl ether) (1.0 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. A mixture of methyl iodide (0.148 g) and THF (2 mL) was added to the reaction mixture at -78°C, and the mixture was stirred under water cooling for 18 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under water cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~65/35) and then by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~80/20) to obtain the title compound (0.150 g).

Reference example B-38 (3R)-3-Amino-8-(2-(difluoromethyl)-5-fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.145 g) and DMF (1 mL), zinc (0.054 g ) and stir at room temperature for 2 hours. A mixture of Reference Example B-37 (0.126 g) and DMF (2 mL), palladium (II) acetate (0.005 g), and Xphos (0.017 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution, water and ethyl acetate. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. To a mixture of the residue and DCM (2 mL), TFA (0.829 g) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. 5 mol/L sodium hydroxide aqueous solution (1.45 mL) was added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=50/50/0~0/100/0~0/80/20) to obtain the title compound (0.025 g) .

Reference Example B-39 Reference Example B-39 was synthesized by the same method as Reference Example B-37, using 5-fluoro-2-hydroxybenzaldehyde instead of 4-fluoro-2-hydroxybenzaldehyde.

Reference Example B-40 Reference Example B-39 was used instead of Reference Example B-37, and Reference Example B-40 was synthesized by the same method as Reference Example B-38.

Reference Example B-41 Reference Example B-41 was synthesized by the same method as Reference Example B-13, using 2-chloro-5-methoxyphenol instead of 2-chloro-5-fluorophenol.

Reference Example B-42 Reference Example B-41 was used instead of Reference Example B-21, and Reference Example B-42 was synthesized by the same method as Reference Example B-22.

Reference example B-43 1-bromo-3-fluoro-2-nitrobenzene was replaced with 1-bromo-3-fluoro-4-methyl-2-nitrobenzene, and 2-chloro-5-fluorophenol was replaced with 2-chloro Phenol was synthesized in Reference Example B-43 by the same method as Reference Example B-13.

Reference example B-44 Reference Example B-43 was used instead of Reference Example B-21, and Reference Example B-44 was synthesized by the same method as Reference Example B-22.

Reference Example B-45 Reference Example B-45 was synthesized by the same method as Reference Example B-13, except that 1-(benzyloxy)-4-bromo-2-fluoro-3-nitrobenzene was used instead of 1-bromo-3-fluoro-2-nitrobenzene, and 2-chlorophenol was used instead of 2-chloro-5-fluorophenol.

Reference example B-46 Reference Example B-45 was used instead of Reference Example B-21, and Reference Example B-46 was synthesized by the same method as Reference Example B-22.

Reference Example B-47 Reference Example B-47 was synthesized by the same method as Reference Example B-13, except that 2-chlorophenol was used instead of 2-chloro-5-fluorophenol and ethyl iodide was used instead of methyl iodide.

Reference Example B-48 Reference Example B-47 was used instead of Reference Example B-21, and Reference Example B-48 was synthesized by the same method as Reference Example B-22.

Reference example B-49 2-Bromo-6-(2-chloro-4,5-difluorophenoxy)-N-methylaniline To the mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.300 g), 2-chloro-4,5-difluorophenol (0.236 g) and NMP (3 mL), add potassium carbonate (0.377 g) , stirred at 110°C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ammonium chloride (1.82 g) and iron powder (0.381 g) were added to a mixture of the residue, ethanol (3 mL) and water (1 mL), and the mixture was stirred at 80°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, water was added. After the mixture was extracted with DCM, the extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate = 98/2~85/15), 2- Bromo-6-(2-chloro-4,5-difluorophenoxy)aniline (0.160 g). To a mixture of the obtained compound (0.160 g) and THF (1 mL), methyllithium (1.04 mol/L in diethyl ether) (0.506 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. A mixture of methyl iodide (0.081 g) and THF (1 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes, and then stirred under ice-cooling for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.135 g).

Reference Example B-50 Reference Example B-49 was used instead of Reference Example B-1, and Reference Example B-50 was synthesized by the same method as Reference Example B-2.

Reference example B-51 Instead of 1-bromo-3-fluoro-2-nitrobenzene, 1-bromo-3,4-difluoro-2-nitrobenzene was used, and in place of 2-chloro-4,5-difluorophenol, 2- (Trifluoromethyl)phenol was synthesized in Reference Example B-51 by the same method as Reference Example B-49.

Reference Example B-52 (3R)-3-amino-7-fluoro-1-methyl-8-(2-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-2-one Zinc (0.126 g) was added to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.347 g) and DMF (2 mL), and the mixture was stirred at room temperature for 1 hour. Reference Example B-51 (0.320 g), palladium (II) acetate (0.010 g), and Xphos (0.042 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. Saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. TFA (2.00 g) was added to the mixture of the residue and DCM (2 mL) under ice-cooling, and stirred at room temperature for 4 hours. 2 mol/L aqueous sodium hydroxide solution (8.8 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 59/39/2~0/98/2), and then purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 98/2~80/20) to obtain the title compound (0.099 g).

Reference Example B-53 Reference Example B-53 was synthesized by the same method as Reference Example B-49, using 1-bromo-4-chloro-3-fluoro-2-nitrobenzene instead of 1-bromo-3-fluoro-2-nitrobenzene and using 2-chloro-5-fluorophenol instead of 2-chloro-4,5-difluorophenol.

Reference Example B-54 Reference Example B-53 was used instead of Reference Example B-1, and Reference Example B-54 was synthesized by the same method as Reference Example B-2.

Reference example B-55 6-Bromo-2-(2-(difluoromethyl)phenoxy)-N,3-dimethylaniline Potassium carbonate (0.364 g) was added to the mixture of 1-bromo-3-fluoro-4-methyl-2-nitrobenzene (0.306 g), 2-hydroxybenzaldehyde (0.167 g) and DMF (3 mL). Stir at 100°C for 2 hours. After the reaction mixture was cooled to room temperature, water, ethyl acetate and toluene were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30) to obtain 2-(3-bromo-6-methyl-2-nitrophenoxy) base) benzaldehyde (0.306 g). Bis(2-methoxyethyl)aminosulfur trifluoride (0.866 g) and ethanol (0.018 g) were added to a mixture of the obtained compound (0.306 g) and DCM (3 mL), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was added to ice-cold aqueous potassium carbonate solution. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~65/35) to obtain 1-bromo-3-(2-(difluoromethyl)phenoxy) )-4-methyl-2-nitrobenzene (0.298 g). Ammonium chloride (1.75 g) and iron powder (0.365 g) were added to a mixture of the obtained compound (0.298 g), ethanol (4.5 mL) and water (1.5 mL), and the mixture was stirred at 80°C for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered through celite. After adding water to the filtrate, the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30) to obtain 6-bromo-2-(2-(difluoromethyl)phenoxy) )-3-methylaniline (0.237 g). To a mixture of the obtained compound (0.237 g) and THF (2 mL), methyllithium (1.04 mol/L in diethyl ether) (0.9 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. A mixture of methane iodide (0.143 g) and THF (1 mL) was added to the reaction mixture at -78°C, and the mixture was stirred under ice-cooling for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under water cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~90/10) to obtain the title compound (0.239 g).

Reference example B-56 Reference Example B-55 was used instead of Reference Example B-5, and Reference Example B-56 was synthesized by the same method as Reference Example B-6.

Reference Example B-57 6-Bromo-2-(2-chloro-5-fluorophenoxy)-N,3-dimethylaniline Potassium carbonate (0.360 g) was added to a mixture of 1-bromo-3-fluoro-4-methyl-2-nitrobenzene (0.305 g), 2-chloro-5-fluorophenol (0.200 g) and DMF (10 mL), and the mixture was stirred at 100°C for 2 hours. After the reaction mixture was cooled to room temperature, water, ethyl acetate and toluene were added. The mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~55/45) to obtain 1-bromo-3-(2-chloro-5-fluorophenoxy)-4-methyl-2-nitrobenzene (0.439 g). To a mixture of the obtained compound (0.439 g), ethanol (4.5 mL) and water (1.5 mL), ammonium chloride (1.74 g) and iron powder (0.362 g) were added and stirred at 80°C for 1.5 hours. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. After adding water to the filtrate, the mixture was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-methylaniline (0.355 g). Methyl lithium (1.04 mol/L in diethyl ether) (1.3 mL) was added to a mixture of the obtained compound (0.355 g) and THF (3 mL) at -78°C, and stirred at the same temperature for 1 hour. A mixture of iodomethane (0.214 g) and THF (1.5 mL) was added to the reaction mixture at -78°C, and stirred under ice cooling for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under water cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~90/10) to obtain the title compound (0.349 g).

Reference Example B-58 (3R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-1,2,3,4-tetrahydroquinolin-2-one Zinc (0.141 g) was added to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.393 g) and DMF (3 mL) under an hydrogen atmosphere, and the mixture was stirred at room temperature for 1.5 hours. A mixture of Reference Example B-57 (0.338 g) and DMF (1 mL), palladium (II) acetate (0.012 g), and Xphos (0.047 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 13 hours. A saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. TFA (2.24 g) was added to the mixture of the residue and DCM (4 mL) under ice-cooling, and stirred at room temperature for 3 hours. A 5 mol/L aqueous sodium hydroxide solution (3.9 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 50/50/0~0/100/0~0/80/20) to obtain the title compound (0.135 g).

Reference Example B-59 Reference Example B-59 was synthesized by the same method as Reference Example B-49, using 2-chlorophenol instead of 2-chloro-4,5-difluorophenol.

Reference example B-60 Reference Example B-59 was used instead of Reference Example B-51, and Reference Example B-60 was synthesized by the same method as Reference Example B-52.

Reference example B-61 2-Bromo-6-(cyclohexyloxy)-N-methylaniline Add sodium hydride (about 60%) (0.280 g) to the mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.770 g), cyclohexanol (0.386 g) and DMF (5 mL), and keep at room temperature Stir for 1 hour. Water, ethyl acetate and n-hexane were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue, ethanol (3 mL) and water (1 mL), ammonium chloride (4.68 g) and iron powder (0.977 g) were added at room temperature, and the mixture was stirred at 80°C for 1.5 hours. The reaction mixture was cooled to room temperature, water was added, the mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30) to obtain 2-bromo-6-(cyclohexyloxy)aniline (0.458 g). To a mixture of the obtained compound (0.458 g) and THF (8 mL), methyllithium (1.04 mol/L in diethyl ether) (1.8 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. A mixture of methane iodide (0.385 g) and THF (2 mL) was added to the reaction mixture at -78°C, followed by stirring at the same temperature for 10 minutes and at room temperature for 1 hour. Methyllithium (1.04 mol/L in diethyl ether) (1.8 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture under ice cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~80/20) to obtain the title compound (0.456 g).

Reference example B-62 (3R)-3-Amino-8-(cyclohexyloxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to the mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.634 g) and DMF (10 mL), zinc (0.231 g ) and stir at room temperature for 2 hours. Reference Example B-61 (0.456 g), palladium (II) acetate (0.018 g), and Xphos (0.077 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was stirred at 80°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution and ethyl acetate were added. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DCM (5 mL), TFA (3.66 g) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. A 5 mol/L sodium hydroxide aqueous solution (10 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: ethyl acetate/methanol=100/0~50/50) to obtain the title compound (0.016 g).

Reference Example B-63 2-Bromo-6-(cyclopentyloxy)-N-methylaniline Sodium hydroxide (about 60%) (0.091 g) was added to a mixture of cyclopentanol (0.196 g) and DMF (4 mL), and the mixture was stirred at room temperature for 30 minutes. 1-Bromo-3-fluoro-2-nitrobenzene (0.500 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium chloride solution, ethyl acetate and n-hexane were added to the reaction mixture under ice cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30), and then purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30) to obtain 1-bromo-3-(cyclopentyloxy)-2-nitrobenzene (0.462 g). To a mixture of the obtained compound (0.462 g), ethanol (5 mL) and water (2 mL), ammonium chloride (2.16 g) and iron powder (0.450 g) were added and stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~0/100) to obtain 2-bromo-6-(cyclopentyloxy)aniline (0.382 g). Methyl lithium (1.04 mol/L in diethyl ether) (1.4 mL) was added to a mixture of the obtained compound (0.382 g) and THF (3 mL) at -78°C, and stirred at the same temperature for 1 hour. A mixture of iodomethane (0.284 g) and THF (1 mL) was added to the reaction mixture at -78°C, stirred at the same temperature for 15 minutes, and stirred under ice cooling for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~90/10) to obtain the title compound (0.218 g).

Reference example B-64 Reference Example B-63 was used instead of Reference Example B-5, and Reference Example B-64 was synthesized by the same method as Reference Example B-6.

Reference example B-65 6-Bromo-2-(2-(difluoromethyl)phenoxy)-3-fluoro-N-methylaniline Add potassium carbonate (1.17 g) to the mixture of 1-bromo-3,4-difluoro-2-nitrobenzene (1.01 g), 2-hydroxybenzaldehyde (0.540 g) and DMF (10 mL), and heat at 100°C Stir for 1 hour. After the reaction mixture was cooled to room temperature, water, ethyl acetate and toluene were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. Bis(2-methoxyethyl)amine sulfur trifluoride (3.76 g) was added to a mixture of the residue, DCM (10 mL) and ethanol (0.078 g), and the mixture was stirred at 40°C for 3.5 hours. The reaction mixture was added to ice-cold aqueous sodium hydroxide solution. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Ethyl acetate, MTBE and water were added to the residue. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~60/40) to obtain 1-bromo-3-(2-(difluoromethyl)phenoxy) )-4-fluoro-2-nitrobenzene (1.07 g). Ammonium chloride (3.93 g) and iron powder (0.821 g) were added to a mixture of the obtained compound (1.07 g), ethanol (10 mL) and water (3 mL), and the mixture was stirred at 80°C for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered through celite. After adding water to the filtrate, the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~70/30) to obtain 6-bromo-2-(2-(difluoromethyl)phenoxy) )-3-chloroaniline (0.963 g). Under an argon environment, add methyllithium (1.04 mol/L in diethyl ether) (3.6 mL) at -78°C to a mixture of the obtained compound (0.957 g) and THF (12 mL). Stir for 30 minutes. Methyl iodide (0.573 g) was added to the reaction mixture at -78°C, followed by stirring at the same temperature for 10 minutes and then under ice-cooling for 30 minutes. To the reaction mixture were added saturated aqueous ammonium chloride solution and ethyl acetate under ice cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate=100/0~95/5) to obtain the title compound (0.915 g).

Reference example B-66 Reference Example B-65 was used instead of Reference Example B-21, and Reference Example B-66 was synthesized by the same method as Reference Example B-22.

Reference Example B-67 6-Bromo-2-(2-chloro-5-fluorophenoxy)-3-fluoro-N-methylaniline Potassium carbonate (1.17 g) was added to a mixture of 1-bromo-3,4-difluoro-2-nitrobenzene (1.02 g), 2-chloro-5-fluorophenol (0.651 g) and DMF (10 mL), and the mixture was stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, water, ethyl acetate and toluene were added. After the mixture was extracted with ethyl acetate, the extract was washed with water and concentrated under reduced pressure. To a mixture of the residue, ethanol (15 mL) and water (5 mL), ammonium chloride (5.72 g) and iron powder (1.20 g) were added, and the mixture was stirred at 80°C for 1.5 hours. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. After adding water to the filtrate, the mixture was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~60/40) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-fluoroaniline (0.916 g). Methyl lithium (1.04 mol/L in diethyl ether) (3.6 mL) was added to the mixture of the obtained compound (0.908 g) and THF (10 mL) at -78°C and stirred at the same temperature for 1 hour. After adding a mixture of iodomethane (0.539 g) and THF (5 mL) to the reaction mixture at -78°C, stir under ice-cooling for 1 hour. Add saturated aqueous ammonium chloride solution and water to the reaction mixture under ice-cooling. Extract the mixture with DCM, and concentrate the extract under reduced pressure. Purify the residue by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~90/10) to obtain the title compound (0.633 g).

Reference Example B-68 Reference Example B-67 was used instead of Reference Example B-21, and Reference Example B-68 was synthesized by the same method as Reference Example B-22.

Reference example B-69 1-bromo-3-fluoro-2-nitrobenzene was replaced with 1-bromo-3-fluoro-4-methyl-2-nitrobenzene, and 2-chloro-5-fluorophenol was replaced with 2-fluoro Phenol was synthesized in Reference Example B-69 by the same method as Reference Example B-13.

Reference Example B-70 (3R)-3-amino-8-(2-fluorophenoxy)-1,7-dimethyl-1,2,3,4-tetrahydroquinolin-2-one Zinc (0.086 g) was added to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.257 g) and DMF (4 mL) in an hydrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. A mixture of Reference Example B-69 (0.186 g) and DMF (1 mL), palladium (II) acetate (0.007 g), and Xphos (0.029 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution and diethyl ether were added to the reaction mixture. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. TFA (1.37 g) was added to the mixture of the residue and DCM (4 mL) under ice-cooling, and stirred at room temperature for 3 hours. A 5 mol/L aqueous sodium hydroxide solution (2.5 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 40/60/0~0/100/0~0/60/40) to obtain the title compound (0.031 g).

Reference Example B-71 Reference Example B-71 was synthesized by the same method as Reference Example B-13, except that 1-bromo-3-fluoro-4-methyl-2-nitrobenzene was used instead of 1-bromo-3-fluoro-2-nitrobenzene, and 3-fluorophenol was used instead of 2-chloro-5-fluorophenol.

Reference example B-72 Reference Example B-71 was used instead of Reference Example B-21, and Reference Example B-72 was synthesized by the same method as Reference Example B-22.

Reference Example B-73 2-Bromo-N-methyl-6-(2-methylphenoxy)aniline Potassium carbonate (0.377 g) was added to a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.300 g), 2-methylphenol (0.147 g) and DMF (3 mL), and the mixture was stirred at 110°C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate, n-hexane and water were added. After the mixture was extracted with ethyl acetate, the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ammonium chloride (1.46 g) and iron powder (0.381 g) were added to a mixture of residue, ethanol (3 mL) and water (1 mL), and the mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 2-bromo-6-(2-methylphenoxy)aniline (0.370 g). Methyl lithium (3.1 mol/L in diethoxymethane) (0.472 mL) was added to the mixture of the obtained compound (0.370 g) and THF (3 mL) at -78°C and stirred at the same temperature for 1 hour. A solution of iodomethane (0.227 g) in THF (1 mL) was added to the reaction mixture at -78°C, stirred at the same temperature for 10 minutes, and stirred for 2 hours under ice cooling. Saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.390 g).

Reference example B-74 (3R)-3-Amino-1-methyl-8-(2-methylphenoxy)-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to the mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.642 g) and DMF (3 mL), zinc (0.187 g ) and stir at room temperature for 1 hour. Reference Example B-73 (0.380 g), palladium (II) acetate (0.015 g), and Xphos (0.062 g) were added to the reaction mixture, and the mixture was stirred at 40° C. for 3 hours. After the reaction mixture was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution and ethyl acetate were added. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DCM (3 mL), TFA (2.97 g) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. A 5 mol/L sodium hydroxide aqueous solution (5.2 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (eluting solvent: ethyl acetate/methanol=98/2~80/20) to obtain the title compound (0.290 g).

Reference example B-75 Reference Example B-75 was synthesized by the same method as Reference Example B-73, except that 5-fluoro-2-methylphenol was used instead of 2-methylphenol.

Reference Example B-76 Reference Example B-75 was used instead of Reference Example B-73, and Reference Example B-76 was synthesized by the same method as Reference Example B-74.

Reference example B-77 1-bromo-3-fluoro-2-nitrobenzene was replaced with 1-bromo-3-fluoro-4-methyl-2-nitrobenzene, and 2-methylphenol was replaced with 2,5-difluoro Phenol was synthesized in Reference Example B-77 by the same method as Reference Example B-73.

Reference example B-78 (3R)-3-Amino-8-(2,5-difluorophenoxy)-1,7-dimethyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to a mixture of zinc (0.156 g) and DMF (1.4 mL), (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.537 g) was added ) and THF (0.7 mL), stirred at room temperature for 1 hour. A mixture of Reference Example B-77 (0.357 g) and THF (1.4 mL), palladium (II) acetate (0.012 g), and Xphos (0.052 g) were added to the reaction mixture, and the mixture was stirred at 40° C. for 2 hours. A saturated aqueous ammonium chloride solution, water, ethyl acetate and n-hexane were added to the reaction mixture under ice-cooling. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate/n-hexane (1/1). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanesulfonic acid (0.314 g) was added to a mixture of the residue, toluene (1.7 mL) and ethanol (1.2 mL), and the mixture was stirred at 80°C for 30 minutes. 5 mol/L sodium hydroxide aqueous solution (0.66 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (eluting solvent: ethyl acetate/methanol=98/2~80/20) to obtain the title compound (0.275 g).

Reference Example C-1 6-Bromo-2-(2-fluorophenoxy)-3-(trifluoromethyl)benzoic acid tert-butyl ester A mixture of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (1.00 g), Boc ₂ O (1.52 g), DMAP (0.043 g) and tert-butanol (10 mL) was stirred at room temperature for 13 hours. The reaction mixture was stirred at 50°C for 2 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The mixture was extracted with ethyl acetate, and the extract was washed with 1 mol/L hydrochloric acid and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Potassium carbonate (0.403 g) was added to a mixture of the residue, 2-fluorophenol (0.163 g) and NMP (5 mL), and the mixture was stirred at 110°C for 4 hours. After the reaction mixture was cooled to room temperature, water, ethyl acetate and n-hexane were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.560 g).

Reference Example C-2 N-(6-bromo-2-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl)-N-methylcarbamic acid tert-butyl ester A mixture of Reference Example C-1 (0.560 g) and hydrogen chloride (4 mol/L in 1,4-dioxane) (3 mL) was stirred at room temperature for 1 hour. The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was stirred at 70°C for 14 hours. Hydrogen chloride (4 mol/L in 1,4-dioxane) (2 mL) was added to the reaction mixture and stirred at 80°C for 6 hours. After the reaction mixture was cooled to room temperature, water was added. The mixture was extracted with ethyl acetate and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. DIPEA (0.171 g) and DPPA (0.365 g) were added to a mixture of the residue, toluene (3 mL) and tert-butanol (2 mL), and stirred at 100°C for 3 hours. DPPA (0.912 g) and DIPEA (0.428 g) were added to the reaction mixture, and stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~60/40), and then purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~60/40) to obtain tert-butyl N-(6-bromo-2-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl)carbamate (0.768 g). To a mixture of the obtained compound (0.497 g), DMF (10 mL) and methyl iodide (0.235 g), sodium hydroxide (about 60%) (0.066 g) was added under ice-cooling, and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution, ethyl acetate and n-hexane were added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~30/70) to obtain the title compound (0.248 g).

Reference example C-3 (3R)-3-Amino-8-(2-fluorophenoxy)-1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to the mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.211 g) and DMF (2 mL), zinc (0.077 g ) and stir at room temperature for 2 hours. Reference Example C-2 (0.248 g), palladium (II) acetate (0.006 g), and Xphos (0.025 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and ethyl acetate. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DCM (2 mL), TFA (1.22 g) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. A 5 mol/L sodium hydroxide aqueous solution (5 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: ethyl acetate/methanol=100/0~50/50) to obtain the title compound (0.026 g).

Reference Example D-1 2-Bromo-6-((2-chlorophenyl)methyl)-N-methylaniline To a mixture of 1-chloro-2-iodobenzene (1.12 g) and THF (5 mL), add isopropylmagnesium chloride (2 mol/L in THF) (2.4 mL) at -40°C, and stir under ice-cooling for 30 minutes. To the reaction mixture, add a mixture of 3-bromo-2-nitrobenzaldehyde (0.540 g) and THF (5 mL) at -40°C, stir at the same temperature for 10 minutes, and stir under ice-cooling for 2 hours. To the reaction mixture, add a saturated aqueous ammonium chloride solution under ice-cooling. The mixture is extracted with ethyl acetate, and the extract is washed with saturated brine. The extract is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5~70/30) to obtain (3-bromo-2-nitrophenyl)(2-chlorophenyl)methanol (0.800 g). To a mixture of the obtained compound (0.800 g), ethanol (6 mL) and water (2 mL), ammonium chloride (3.12 g) and iron powder (0.652 g) were added and stirred at 80°C for 1.5 hours. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. After adding water to the filtrate, the mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5~70/30) to obtain (2-amino-3-bromophenyl)(2-chlorophenyl)methanol (0.670 g). TFA (2.44 g) and triethylsilane (0.498 g) were added to the mixture of the obtained compound (0.670 g) and DCM (5 mL), and stirred at room temperature for 13 hours. 5 mol/L sodium hydroxide aqueous solution (4.3 mL) was added to the reaction mixture under ice cooling, and stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 2-bromo-6-(2-chlorophenyl)aniline (0.480 g). Methyl lithium (3.1 mol/L in diethoxymethane) (0.574 mL) was added to the mixture of the obtained compound (0.480 g) and THF (5 mL) at -78°C, and stirred at the same temperature for 1 hour. Methyl iodide (0.276 g) was added to the reaction mixture at -78°C, stirred at the same temperature for 10 minutes, and stirred under ice cooling for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.460 g).

Reference example D-2 (3R)-3-Amino-8-((2-chlorophenyl)methyl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to the mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.731 g) and DMF (5 mL), zinc (0.213 g ) and stir at room temperature for 1 hour. Reference Example D-1 (0.460 g), palladium (II) acetate (0.017 g), and Xphos (0.071 g) were added to the reaction mixture, and the mixture was stirred at 40° C. for 6 hours. After the reaction mixture was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution and ethyl acetate were added. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. TFA (3.38 g) was added to the mixture of the residue and DCM (5 mL), and the mixture was stirred at room temperature for 2 hours. A 5 mol/L sodium hydroxide aqueous solution (6.0 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate/methanol = 98/2~80/20) to obtain the title compound (0.120 g).

Reference example D-3 2-Bromo-6-((2-chloro-5-fluorophenyl)methyl)-N-methylaniline To a mixture of 1-chloro-4-fluoro-2-iodobenzene (1.13 g) and THF (4.7 mL), add isopropylmagnesium chloride (2 mol/L in THF) (2.2 mL) at -40°C. Stir under ice cooling for 30 minutes. A mixture of 3-bromo-2-nitrobenzaldehyde (0.506 g) and THF (4.7 mL) was added to the reaction mixture at -40°C, stirred at the same temperature for 10 minutes, and stirred under ice-cooling for 1.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5~70/30) to obtain (3-bromo-2-nitrophenyl) (2-chloro-5 -Fluorophenyl)methanol (0.997 g). Ammonium chloride (2.94 g) and iron powder (0.615 g) were added to a mixture of the obtained compound (0.997 g), ethanol (5.7 mL) and water (1.9 mL), and the mixture was stirred at 80°C for 30 minutes. After the reaction mixture was cooled to room temperature, it was filtered through celite. After adding water to the filtrate, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was suspended in DCM. The supernatant of the suspension was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5~70/30) to obtain (2-amino-3-bromophenyl) ( 2-Chloro-5-fluorophenyl)methanol (0.106 g). The remaining insoluble matter in the suspension was washed with water and n-hexane and dried under reduced pressure to obtain (2-amino-3-bromophenyl)(2-chloro-5-fluorophenyl)methanol (0.635 g). To a mixture of (2-amino-3-bromophenyl)(2-chloro-5-fluorophenyl)methanol (0.740 g) and DCM (5.4 mL), add TFA (2.55 g) and triethylsilane ( 0.521 g) and stirred at room temperature for 24 hours. A 5 mol/L sodium hydroxide aqueous solution (4.5 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 2-bromo-6-(2-chloro-5-fluorobenzyl)aniline. (0.584 g). To a mixture of the obtained compound (0.584 g) and THF (5.7 mL), methyllithium (1.04 mol/L in diethyl ether) (1.96 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. Methyl iodide (0.316 g) was added to the reaction mixture at -78°C, followed by stirring at the same temperature for 10 minutes and then under ice-cooling for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.517 g).

Reference Example D-4 (3R)-3-amino-8-((2-chloro-5-fluorophenyl)methyl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one In an atmosphere of hydrogen, a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.777 g) and THF (1.0 mL) was added to a mixture of zinc (0.226 g) and DMF (2.0 mL), and the mixture was stirred at room temperature for 1 hour. A mixture of Reference Example D-3 (0.517 g) and THF (2.0 mL), palladium (II) acetate (0.018 g), and Xphos (0.075 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 21 hours. A saturated aqueous ammonium chloride solution, water, ethyl acetate, and n-hexane were added to the reaction mixture under ice cooling. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate/n-hexane (1/1). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanesulfonic acid (0.454 g) was added to the mixture of the residue, toluene (2.5 mL) and ethanol (1.6 mL), and stirred at 70°C for 2 hours. 5 mol/L aqueous sodium hydroxide solution (1.0 mL) was added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate/methanol = 98/2/0~0/100/0~0/80/20) to obtain the title compound (0.232 g).

Reference example D-5 Reference Example D-5 was synthesized by the same method as Reference Example D-1 except that 1-iodo-2-(trifluoromethyl)benzene was used instead of 1-chloro-2-iodobenzene.

Reference example D-6 Reference Example D-5 was used instead of Reference Example D-3, and Reference Example D-6 was synthesized by the same method as Reference Example D-4.

Reference example D-7 Reference Example D-7 was synthesized by the same method as Reference Example D-1 except that 1-chloro-2-iodobenzene was used instead of 1-chloro-2-iodobenzene.

Reference example D-8 Reference Example D-7 was used instead of Reference Example D-3, and Reference Example D-8 was synthesized by the same method as Reference Example D-4.

Reference Example D-9 Reference Example D-9 was synthesized by the same method as Reference Example D-1, except that 1-(difluoromethyl)-2-iodobenzene was used instead of 1-chloro-2-iodobenzene.

Reference Example D-10 (3R)-3-amino-8-((2-(difluoromethyl)phenyl)methyl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one In an atmosphere of hydrogen, a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (0.221 g) and THF (0.3 mL) was added to a mixture of zinc (0.064 g) and DMF (0.6 mL), and the mixture was stirred at room temperature for 1 hour. A mixture of Reference Example D-9 (0.146 g) and THF (0.6 mL), palladium (II) acetate (0.005 g), and Xphos (0.021 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours and at 40°C for 3 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution, water, ethyl acetate and n-hexane were added to the reaction mixture. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate/n-hexane (1/1). The extract was washed with water and concentrated under reduced pressure. Methanesulfonic acid (0.129 g) was added to the mixture of residue, toluene (0.75 mL) and ethanol (0.45 mL), and stirred at 70°C for 3 hours. After the reaction mixture was cooled to room temperature, it was separated with water and ethyl acetate. The aqueous layer was separated, ethyl acetate was added, and a saturated aqueous sodium bicarbonate solution was added under stirring. The organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (0.032 g).

Reference example D-11 6-Bromo-2-((2-chloro-5-fluorophenyl)methyl)-3-fluoro-N-methylaniline To a mixture of 1-chloro-4-fluoro-2-iodobenzene (0.620 g) and THF (3 mL), add isopropylmagnesium chloride (2 mol/L in THF) (1.21 mL) at -40°C. Stir under ice cooling for 30 minutes. A mixture of 3-bromo-6-fluoro-2-nitrobenzaldehyde (0.300 g) and THF (3 mL) was added to the reaction mixture at -40°C, stirred at the same temperature for 10 minutes, and stirred under ice-cooling for 1 hour. . A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~75/25) to obtain (3-bromo-6-fluoro-2-nitrophenyl) (2 -Chloro-5-fluorophenyl)methanol (0.424 g). Ammonium chloride (1.50 g) and iron powder (0.313 g) were added to a mixture of the obtained compound (0.424 g), ethanol (3 mL) and water (1 mL), and the mixture was stirred at 80°C for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered through celite. After adding water to the filtrate, the mixture was extracted with ethyl acetate. Wash the extract with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain (2-amino-3-bromo-6-fluorophenyl)(2-chloro-5-fluorophenyl)methanol (0.328 g). To a mixture of the obtained compound (0.161 g) and DCM (1.6 mL), boron trifluoride diethyl ether complex (0.098 g) and triethylsilane (0.081 g) were added, and the mixture was stirred at room temperature for 15 hours. TFA (0.527 g) was added to the reaction mixture, and the mixture was refluxed for 8 hours. A 5 mol/L sodium hydroxide aqueous solution (1 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~85/15) to obtain 6-bromo-2-(2-chloro-5-fluorobenzyl)- 3-Fluoroaniline (0.073 g). To a mixture of the obtained compound (0.073 g) and THF (2 mL), methyllithium (3.1 mol/L in diethoxymethane) (0.078 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.037 g) was added to the reaction mixture at -78°C, followed by stirring at the same temperature for 10 minutes and then under ice-cooling for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~90/10) to obtain the title compound (0.051 g).

Reference Example D-12 Reference Example D-11 was used instead of Reference Example D-9, and Reference Example D-12 was synthesized by the same method as Reference Example D-10.

Reference example D-13 6-Bromo-3-chloro-2-((2-chloro-5-fluorophenyl)methyl)-N-methylaniline To a mixture of 1-chloro-4-fluoro-2-iodobenzene (0.769 g) and THF (3.7 mL), add isopropylmagnesium chloride (2 mol/L in THF) (1.5 mL) at -40°C. Stir under ice cooling for 30 minutes. A mixture of Reference Example E-1 (0.397 g) and THF (3.7 mL) was added to the reaction mixture at -40°C, stirred at the same temperature for 10 minutes, and stirred under ice-cooling for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue, ethanol (8.2 mL) and water (2.7 mL), ammonium chloride (2.01 g) and iron powder (0.419 g) were added, and the mixture was stirred at 80°C for 30 minutes. After the reaction mixture was cooled to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. DCM and n-hexane were added to the residue, and the insoluble matter was filtered out. The obtained solid was washed with n-hexane and concentrated under reduced pressure to obtain (2-amino-3-bromo-6-chlorophenyl)(2-chloro-5-fluorophenyl)methanol (0.455 g) . To a mixture of the obtained compound (0.455 g) and 1,2-dichloroethane (3 mL), TFA (1.42 g) and triethylsilane (0.290 g) were added, and the mixture was stirred at 50°C for 30 minutes and at 70°C. 2.5 hours. A 5 mol/L sodium hydroxide aqueous solution (2.5 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15), and 6-bromo-3-chloro-2-( was obtained in the form of a mixture with impurities 2-Chloro-5-fluorobenzyl)aniline. n-hexane was added to the product, and the mixture was stirred under ice-cooling. The insoluble matter was filtered off, washed with n-hexane, and the filtrate and washing liquid were combined and concentrated under reduced pressure. n-hexane was added to the residue, and the supernatant was separated and concentrated under reduced pressure to obtain 6-bromo-3-chloro-2-(2-chloro-5-fluorobenzyl)aniline (0.263 g). To a mixture of the obtained compound (0.262 g) and THF (2.1 mL), methyllithium (1.04 mol/L in diethyl ether) (0.718 mL) was added at -78°C, and the mixture was stirred at the same temperature for 45 minutes. Methyl iodide (0.116 g) was added to the reaction mixture at -78°C, followed by stirring at the same temperature for 10 minutes and then under ice-cooling for 45 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.228 g).

Reference example D-14 Reference Example D-13 was used instead of Reference Example D-3, and Reference Example D-14 was synthesized by the same method as Reference Example D-4.

Reference Example D-15 6-Bromo-2-((2-chlorophenyl)methyl)-N,3-dimethylaniline To a mixture of 1-chloro-2-iodobenzene (0.782 g) and THF (4 mL), add isopropylmagnesium chloride (2 mol/L in THF) (1.64 mL) at -40°C, and stir under ice-cooling for 30 minutes. To the reaction mixture, add a mixture of Reference Example E-2 (0.400 g) and THF (4 mL) at -40°C, stir at the same temperature for 10 minutes, and stir under ice-cooling for 1.5 hours. To the reaction mixture, add a saturated aqueous ammonium chloride solution and water under ice-cooling. The mixture is extracted with DCM, and the extract is concentrated under reduced pressure. To the mixture of the residue, ethanol (9 mL) and water (3 mL), ammonium chloride (2.19 g) and iron powder (0.458 g) were added, and the mixture was stirred at 80°C for 1.5 hours. After the reaction mixture was cooled to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5~70/30) to obtain (2-amino-3-bromo-6-methylphenyl)(2-chlorophenyl)methanol (0.390 g). To the mixture of the obtained compound (0.360 g) and 1,2-dichloroethane (5 mL), TFA (1.26 g) and triethylsilane (0.256 g) were added, and the mixture was stirred at 70°C for 4 hours. To the reaction mixture, 5 mol/L sodium hydroxide aqueous solution (2.2 mL) was added under ice cooling and stirred at room temperature for 10 minutes. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~80/20) to obtain 6-bromo-2-(2-chlorobenzyl)-3-methylaniline (0.350 g). Methyl lithium (3.1 mol/L in diethoxymethane) (0.4 mL) was added to the mixture of the obtained compound (0.350 g) and THF (3 mL) at -78°C and stirred at the same temperature for 1 hour. After adding iodomethane (0.192 g) to the reaction mixture at -78°C, stir at the same temperature for 10 minutes and stir under ice-cooling for 1 hour. Add saturated aqueous ammonium chloride solution to the reaction mixture under ice-cooling. Extract the mixture with DCM, and concentrate the extract under reduced pressure. Purify the residue by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.330 g).

Reference example D-16 (3R)-3-Amino-8-((2-chlorophenyl)methyl)-1,7-dimethyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to the mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.502 g) and DMF (2 mL), zinc (0.146 g ) and stir at room temperature for 1 hour. A mixture of Reference Example D-15 (0.330 g) and DMF (2 mL), palladium (II) acetate (0.011 g), and Xphos (0.048 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and ethyl acetate. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. TFA (2.32 g) was added to a mixture of the residue and 1,2-dichloroethane (5 mL), and the mixture was stirred at 70°C for 2 hours. A 5 mol/L sodium hydroxide aqueous solution (4.1 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate/methanol=98/2~80/20) to obtain the title compound (0.009 g).

Reference Example D-17 6-Bromo-2-((2-chloro-5-fluorophenyl)methyl)-N,3-dimethylaniline To a mixture of 1-chloro-4-fluoro-2-iodobenzene (1.05 g) and THF (5 mL), add isopropylmagnesium chloride (2 mol/L in THF) (2.05 mL) at -40°C, and stir under ice-cooling for 30 minutes. To the reaction mixture, add a mixture of Reference Example E-2 (0.500 g) and THF (5 mL) at -40°C, stir at the same temperature for 10 minutes, and stir under ice-cooling for 1.5 hours. To the reaction mixture, add a saturated aqueous ammonium chloride solution and water under ice-cooling. The mixture is extracted with DCM, and the extract is concentrated under reduced pressure. To a mixture of the residue, ethanol (9 mL) and water (3 mL), ammonium chloride (2.74 g) and iron powder (0.572 g) were added, and the mixture was stirred at 80°C for 1.5 hours. After the reaction mixture was cooled to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in n-hexane and the solid was filtered. The obtained solid was concentrated under reduced pressure to obtain (2-amino-3-bromo-6-methylphenyl)(2-chloro-5-fluorophenyl)methanol (0.540 g). To a mixture of the obtained compound (0.540 g) and 1,2-dichloroethane (5 mL), TFA (1.79 g) and triethylsilane (0.364 g) were added, and the mixture was stirred at 70°C for 10 hours. To the reaction mixture, 5 mol/L sodium hydroxide aqueous solution (4.0 mL) was added under ice cooling and stirred at room temperature for 10 minutes. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 6-bromo-2-(2-chloro-5-fluorobenzyl)-3-methylaniline (0.580 g). Methyl lithium (3.1 mol/L in diethoxymethane) (0.559 mL) was added to the mixture of the obtained compound (0.580 g) and THF (5 mL) at -78°C and stirred at the same temperature for 1 hour. After adding iodomethane (0.268 g) to the reaction mixture at -78°C, stir at the same temperature for 10 minutes and stir under ice-cooling for 1 hour. Add saturated aqueous ammonium chloride solution and water to the reaction mixture under ice-cooling. Extract the mixture with DCM, and concentrate the extract under reduced pressure. Purify the residue by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.410 g).

Reference example D-18 Reference Example D-17 was used instead of Reference Example D-15, and Reference Example D-18 was synthesized by the same method as Reference Example D-16.

Reference example D-19 6-Bromo-2-((2-chlorophenyl)methyl)-3-fluoro-N-methylaniline To a mixture of 1-chloro-2-iodobenzene (0.577 g) and THF (3 mL), add isopropylmagnesium chloride (2 mol/L in THF) (1.21 mL) at -40°C, and stir under ice-cooling 30 minutes. A mixture of 3-bromo-6-fluoro-2-nitrobenzaldehyde (0.300 g) and THF (3 mL) was added to the reaction mixture at -40°C, stirred at the same temperature for 10 minutes, and stirred under ice-cooling for 1 hour. . A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, ethanol (3 mL) and water (1 mL), ammonium chloride (1.62 g) and iron powder (0.338 g) were added, and the mixture was stirred at 80°C for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered through celite. After adding water to the filtrate, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue and DCM (4 mL), TFA (1.38 g) and triethylsilane (0.281 g) were added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was refluxed overnight. A 5 mol/L sodium hydroxide aqueous solution (2.42 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~92/8) to obtain 6-bromo-2-(2-chlorobenzyl)-3-fluoroaniline. (0.192 g). To a mixture of the obtained compound (0.192 g) and THF (2 mL), methyllithium (3.1 mol/L in diethoxymethane) (0.217 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.104 g) was added to the reaction mixture at -78°C, followed by stirring at the same temperature for 10 minutes and then under ice-cooling for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~92/8) to obtain the title compound (0.178 g).

Reference Example D-20 Reference Example D-19 was used instead of Reference Example D-9, and Reference Example D-20 was synthesized by the same method as Reference Example D-10.

Reference example D-21 Reference Example D-21 was synthesized by the same method as Reference Example D-19, using 1-iodo-2-(trifluoromethyl)benzene instead of 1-chloro-2-iodobenzene.

Reference example D-22 Reference Example D-21 was used instead of Reference Example D-9, and Reference Example D-22 was synthesized by the same method as Reference Example D-10.

Reference Example D-23 Reference Example D-23 was synthesized by the same method as Reference Example D-19, using Reference Example E-1 instead of 3-bromo-6-fluoro-2-nitrobenzaldehyde.

Reference example D-24 Reference Example D-23 was used instead of Reference Example D-9, and Reference Example D-24 was synthesized by the same method as Reference Example D-10.

Reference Example D-25 6-Bromo-3-fluoro-N-methyl-2-((2-methylphenyl)methyl)aniline To a mixture of 1-iodo-2-methylbenzene (0.527 g) and THF (3 mL), add isopropylmagnesium chloride (2 mol/L in THF) (1.21 mL) at -40°C, and stir under ice-cooling for 30 minutes. To the reaction mixture, add a mixture of 3-bromo-6-fluoro-2-nitrobenzaldehyde (0.300 g) and THF (3 mL) at -40°C, stir at the same temperature for 10 minutes, and stir under ice-cooling for 1 hour. To the reaction mixture, add a saturated aqueous ammonium chloride solution and water under ice-cooling. The mixture is extracted with ethyl acetate, and the extract is washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, ethanol (3 mL) and water (1 mL), ammonium chloride (1.62 g) and iron powder (0.337 g) were added, and the mixture was stirred at 80°C for 1.5 hours. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. After adding water to the filtrate, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue and DCM (2 mL), TFA (0.669 g) and triethylsilane (0.136 g) were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, 5 mol/L sodium hydroxide aqueous solution (1.18 mL) was added under ice cooling and stirred at room temperature for 10 minutes. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~90/10) to obtain 6-bromo-3-fluoro-2-(2-methylbenzyl)aniline (0.149 g). Methyl lithium (3.1 mol/L in diethoxymethane) (0.180 mL) was added to the mixture of the obtained compound (0.149 g) and THF (2 mL) at -78°C and stirred at the same temperature for 30 minutes. After adding iodomethane (0.086 g) to the reaction mixture at -78°C, stir at the same temperature for 10 minutes and stir under ice-cooling for 1 hour. Add saturated aqueous ammonium chloride solution and water to the reaction mixture under ice-cooling. Extract the mixture with DCM, and concentrate the extract under reduced pressure. Purify the residue by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~90/10) to obtain the title compound (0.138 g).

Reference Example D-26 Reference Example D-25 was used instead of Reference Example D-9, and Reference Example D-26 was synthesized by the same method as Reference Example D-10.

Reference example D-27 6-Bromo-3-chloro-2-((2-fluorophenyl)methyl)-N-methylaniline To a mixture of 1-fluoro-2-iodobenzene (0.666 g) and THF (3.7 mL), add isopropyl magnesium chloride (2 mol/L in THF) (1.50 mL) at -40°C, and stir under ice-cooling for 50 minute. A mixture of Reference Example E-1 (0.397 g) and THF (3.7 mL) was added to the reaction mixture at -40°C, stirred at the same temperature for 10 minutes, and stirred under ice-cooling for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue, ethanol (8.2 mL) and water (2.7 mL), ammonium chloride (2.01 g) and iron powder (0.419 g) were added, and the mixture was stirred at 80°C for 30 minutes. After the reaction mixture was cooled to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in n-hexane, and the solid was filtered. The obtained solid was dried under reduced pressure to obtain (2-amino-3-bromo-6-chlorophenyl)(2-fluorophenyl)methanol (0.471 g). To a mixture of the obtained compound (0.470 g) and DCM (1.4 mL), TFA (1.62 g) and triethylsilane (0.331 g) were added, and the mixture was refluxed for 1.5 hours. A 5 mol/L sodium hydroxide aqueous solution (2.9 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 6-bromo-3-chloro-2-(2-fluorobenzyl)aniline. (0.298 g). To a mixture of the obtained compound (0.297 g) and THF (2.9 mL), methyllithium (1.04 mol/L in diethyl ether) (0.999 mL) was added at -78°C, and the mixture was stirred at the same temperature for 45 minutes. Methyl iodide (0.161 g) was added to the reaction mixture at -78°C, followed by stirring at the same temperature for 10 minutes and then under ice-cooling for 45 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.297 g).

Reference example D-28 Reference Example D-27 was used instead of Reference Example D-3, and Reference Example D-28 was synthesized by the same method as Reference Example D-4.

Reference Example D-29 6-Bromo-3-chloro-2-(3-fluorophenyl)-N-methylaniline To a mixture of 1-fluoro-3-iodobenzene (0.666 g) and THF (3.7 mL), add isopropylmagnesium chloride (2 mol/L in THF) (1.50 mL) at -40°C, and stir under ice-cooling for 50 minutes. To the reaction mixture, add a mixture of Reference Example E-1 (0.397 g) and THF (3.7 mL) at -40°C, stir at the same temperature for 10 minutes, and stir under ice-cooling for 30 minutes. To the reaction mixture, add a saturated aqueous ammonium chloride solution and water under ice-cooling. The mixture is extracted with DCM, and the extract is concentrated under reduced pressure. To a mixture of the residue, ethanol (8.2 mL) and water (2.7 mL), ammonium chloride (2.01 g) and iron powder (0.419 g) were added, and the mixture was stirred at 80°C for 30 minutes. After the reaction mixture was cooled to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in n-hexane and the solid was filtered. The obtained solid was dried under reduced pressure to obtain (2-amino-3-bromo-6-chlorophenyl)(3-fluorophenyl)methanol (0.471 g). To a mixture of the obtained compound (0.470 g) and DCM (1.4 mL), TFA (1.62 g) and triethylsilane (0.331 g) were added, and the mixture was refluxed for 2 hours. Add 5 mol/L sodium hydroxide aqueous solution (2.9 mL) to the reaction mixture under ice-cooling and stir at room temperature for 10 minutes. Extract the mixture with DCM and concentrate the extract under reduced pressure. Purify the residue by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 6-bromo-3-chloro-2-(3-fluorobenzyl)aniline in the form of a mixture with impurities. Add n-hexane to the product and let stand under ice-cooling. Filter out insoluble matter and concentrate the filtrate under reduced pressure to obtain 6-bromo-3-chloro-2-(3-fluorobenzyl)aniline (0.369 g). To the mixture of the obtained compound (0.369 g) and THF (3.6 mL), methyl lithium (1.04 mol/L in diethyl ether) (1.24 mL) was added at -78°C and stirred at the same temperature for 45 minutes. Methyl iodide (0.200 g) was added to the reaction mixture at -78°C, stirred at the same temperature for 10 minutes, and stirred under ice-cooling for 45 minutes. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.272 g).

Reference Example D-30 Reference Example D-29 was used instead of Reference Example D-3, and Reference Example D-30 was synthesized by the same method as Reference Example D-4.

Reference Example D-31 Reference Example E-2 was used instead of Reference Example E-1, and Reference Example D-31 was synthesized by the same method as Reference Example D-27.

Reference example D-32 Reference Example D-31 was used instead of Reference Example D-3, and Reference Example D-32 was synthesized by the same method as Reference Example D-4.

Reference example D-33 Reference Example D was synthesized by the same method as Reference Example D-27, replacing 1-fluoro-2-iodobenzene with 1-fluoro-3-iodobenzene, and replacing Reference Example E-1 with Reference Example E-2. -33.

Reference example D-34 Reference Example D-33 was used instead of Reference Example D-3, and Reference Example D-34 was synthesized by the same method as Reference Example D-4.

Reference Example D-35 2-Bromo-6-(5-fluoro-2-methylbenzyl)-N-methylaniline To a mixture of 4-fluoro-2-iodo-1-methylbenzene (0.677 g) and THF (3 mL), add isopropylmagnesium chloride (2 mol/L in THF) (1.44 mL) at -40°C, and stir under ice-cooling for 30 minutes. To the reaction mixture, add a mixture of 3-bromo-2-nitrobenzaldehyde (0.330 g) and THF (3 mL) at -40°C, stir at the same temperature for 10 minutes, and stir under ice-cooling for 1.5 hours. To the reaction mixture, add a saturated aqueous ammonium chloride solution and water under ice-cooling. The mixture is extracted with DCM, and the extract is concentrated under reduced pressure. To the mixture of the residue, ethanol (6 mL) and water (2 mL), ammonium chloride (1.92 g) and iron powder (0.401 g) were added, and the mixture was stirred at 80°C for 1.5 hours. After the reaction mixture was cooled to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~80/20) to obtain (2-amino-3-bromophenyl)(5-fluoro-2-methylphenyl)methanol (0.550 g). To the mixture of the obtained compound (0.550 g) and DCM (5 mL), TFA (1.64 g) and triethylsilane (0.334 g) were added, and the mixture was stirred at room temperature for 13 hours. To the reaction mixture, 5 mol/L sodium hydroxide aqueous solution (3.0 mL) was added under ice cooling and stirred at room temperature for 10 minutes. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 2-bromo-6-(5-fluoro-2-methylbenzyl)aniline (0.480 g). Methyl lithium (3.0 mol/L in diethoxymethane) (0.510 mL) was added to the mixture of the obtained compound (0.480 g) and THF (5 mL) at -78°C and stirred at the same temperature for 30 minutes. After adding iodomethane (0.245 g) to the reaction mixture at -78°C, stir at the same temperature for 10 minutes and under ice-cooling for 1 hour. Add saturated aqueous ammonium chloride solution to the reaction mixture under ice-cooling. Extract the mixture with DCM, and concentrate the extract under reduced pressure. Purify the residue by Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.520 g).

Reference example D-36 Reference Example D-35 was used instead of Reference Example D-15, and Reference Example D-36 was synthesized by the same method as Reference Example D-16.

Reference example E-1 3-Bromo-6-chloro-2-nitrobenzaldehyde To a mixture of 5-bromo-2-chlorobenzaldehyde (6.00 g) and concentrated sulfuric acid (41.6 g), slowly add a mixture of 70% nitric acid (4.92 g) and concentrated sulfuric acid (51.1 g) under ice cooling. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was slowly added to ice water. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), n-hexane (30 mL) was added, and the mixture was stirred at room temperature for 30 minutes and under ice-cooling for 30 minutes. The insoluble matter was filtered off, and the obtained solid was dried under reduced pressure to obtain the title compound (3.10 g).

Reference example E-2 Reference Example E-2 was synthesized by the same method as Reference Example E-1 except that 5-bromo-2-methylbenzaldehyde was used instead of 5-bromo-2-chlorobenzaldehyde.

Reference Example F-1 Reference Example F-1 was synthesized by the same method as Reference Example B-73, except that 1-bromo-3-fluoro-2-nitrobenzene was replaced with 1-bromo-4-chloro-3-fluoro-2-nitrobenzene and 2,5-difluorophenol was replaced with 2-methylphenol.

Reference example F-2 (3R)-3-Amino-7-chloro-8-(2,5-difluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon environment, to a mixture of zinc (0.089 g) and DMF (0.8 mL), (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.306 g) was added ) and DMF (0.4 mL), stirred at room temperature for 1 hour. A mixture of Reference Example F-1 (0.216 g) and DMF (0.8 mL), palladium (II) acetate (0.007 g), and Xphos (0.030 g) were added to the reaction mixture, and the mixture was stirred at 40° C. for 3 hours. A saturated aqueous ammonium chloride solution, water, ethyl acetate and n-hexane were added to the reaction mixture under ice-cooling. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate/n-hexane (1/1). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanesulfonic acid (0.179 g) was added to a mixture of the residue, toluene (1.0 mL) and ethanol (0.7 mL), and the mixture was stirred at 80°C for 0.5 hours. A 5 mol/L sodium hydroxide aqueous solution (0.375 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified using Method A (eluting solvent: ethyl acetate/methanol=98/2~80/20) to obtain the title compound (0.084 g).

Reference example F-3 Instead of 1-bromo-3-fluoro-2-nitrobenzene, 1-bromo-3-fluoro-4-methyl-2-nitrobenzene was used, and in place of 2-hydroxybenzaldehyde, 4-fluoro-2-nitrobenzene was used. Hydroxybenzaldehyde was synthesized in Reference Example F-3 by the same method as Reference Example B-17.

Reference example F-4 Reference Example F-3 was used instead of Reference Example F-1, and Reference Example F-4 was synthesized by the same method as Reference Example F-2.

Reference example F-5 (4-bromo-2-(2-chloro-5-fluorophenoxy)-3-(methylamino)phenyl)methanol To a mixture of 4-bromo-2-fluorobenzyl alcohol (3.00 g) and DMF (30 mL), sodium hydroxide (approximately 60%) (0.761 g) was added under ice cooling, and the mixture was stirred at room temperature for 10 minutes. 4-methoxybenzyl chloride (2.75 g) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution, water, ethyl acetate and n-hexane were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~80/20) to obtain 4-bromo-2-fluoro-1-(((4-methoxy Phenyl)methoxy)methoxy)benzene (4.96 g). To a mixture of the obtained compound (4.76 g) and THF (50 mL), LDA (1.07 mol/L in n-hexane/THF) (22 mL) was added at -78°C, and stirred at the same temperature for 1 hour. DMF (3.21 g) was added to the reaction mixture at -78°C, and stirred at the same temperature for 0.5 hours. After adding 2 mol/L hydrochloric acid (40 mL) to the reaction mixture at -20°C, the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with n-hexane, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Potassium carbonate (4.05 g) was added to a mixture of the residue, NMP (40 mL) and 2-chloro-5-fluorophenol (2.25 g), and the mixture was stirred at 110°C for 3 hours. After the reaction mixture was cooled to room temperature, water, ethyl acetate and n-hexane were added, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5~80/20) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy) -3-(((4-methoxyphenyl)methoxy)methyl)benzaldehyde (5.00 g). To the mixture of the obtained compound (5.00 g), MeCN (22.5 mL) and DMSO (0.977 g), concentrated sulfuric acid (0.613 g) was added under an ice-salt bath. A mixture of sodium hypochlorite (80%) (1.41 g) and water (7.5 mL) was added to the mixture in a salt ice bath, and stirred at the same temperature for 0.5 hours. A saturated aqueous sodium sulfite solution (1.5 mL) was added to the reaction mixture in a salt ice bath, and stirred at room temperature for 10 minutes. Water was added to the mixture, and extraction was performed with n-hexane/ethyl acetate (1/1). Wash the extract with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. TEA (2.11 g) and DPPA (4.31 g) were added to a mixture of the residue and DMF (25 mL), and the mixture was stirred at room temperature for 2 hours. A 5 mol/L sodium hydroxide aqueous solution (8.3 mL) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 0.5 hours. The mixture was extracted with n-hexane/ethyl acetate (1/1). Wash the extract with saturated ammonium chloride aqueous solution, water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~80/20) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy) -3-(((4-methoxyphenyl)methoxy)methyl)aniline (2.80 g). To a mixture of the obtained compound (2.80 g) and ethyl acetate (28 mL), pyridine (0.617 g) and anhydrous trifluoroacetic acid (1.64 g) were added in an ice-salt bath, and the mixture was stirred at the same temperature for 0.5 hours. Methanol (0.192 g) and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Methyl iodide (1.28 g) and potassium carbonate (1.66 g) were added to a mixture of the residue and DMF (14 mL), and the mixture was stirred at room temperature for 3 hours. Water, ethyl acetate and n-hexane were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. A 5 mol/L sodium hydroxide aqueous solution (2.4 mL) was added to a mixture of the residue, methanol (14 mL) and THF (14 mL), and the mixture was stirred at 60°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy) -3-(((4-methoxyphenyl)methoxy)methoxy)-N-methylaniline (2.50 g). To a mixture of the obtained compound (1.50 g), DCM (15 mL) and water (0.15 mL), 2,3-dichloro-5,6-dicyano-p-benzoquinone (0.779 g) was added under ice cooling. Stir at the same temperature for 2 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane/ethyl acetate = 90/10~60/40) to obtain the title compound (0.920 g).

Reference example F-6 Reference Example F-5 was used instead of Reference Example F-1, and Reference Example F-6 was synthesized by the same method as Reference Example F-2.

Reference example F-7 6-Bromo-2-(2-chloro-5-fluorophenoxy)-3-(difluoromethyl)-N-methylaniline To the resulting mixture of 4-bromo-1-(difluoromethyl)-2-fluorobenzene (0.800 g) and THF (8 mL), add LDA (1.07 mol/L in n-hexane/THF) at -78°C. (5.5 mL) and stirred at the same temperature for 1 hour. DMF (0.780 g) was added to the reaction mixture at -78°C, and stirred at the same temperature for 0.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture at -78°C, and stirred at room temperature for 10 minutes. The mixture was extracted with n-hexane, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Potassium carbonate (0.721 g) was added to a mixture of the residue, NMP (5 mL) and 2-chloro-5-fluorophenol (0.535 g), and the mixture was stirred at 110°C for 2 hours. After the reaction mixture was cooled to room temperature, water, ethyl acetate and n-hexane were added, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~80/20) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy) -3-(Difluoromethyl)benzaldehyde (0.790 g). To the mixture of the obtained compound (0.790 g), MeCN (3.6 mL) and DMSO (0.195 g), concentrated sulfuric acid (0.122 g) was added under an ice-salt bath. A mixture of sodium hypochlorite (80%) (0.282 g) and water (1.2 mL) was added to the mixture in a salt ice bath, and stirred at the same temperature for 0.5 hours. Sodium sulfite aqueous solution (0.24 mL) was added to the reaction mixture under an ice-salt bath, and the mixture was stirred at room temperature for 10 minutes. Water was added to the mixture, and extraction was performed with n-hexane/ethyl acetate (1/1). Wash the extract with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. TEA (0.420 g) and DPPA (0.856 g) were added to a mixture of the residue and DMF (4 mL), and the mixture was stirred at room temperature for 2 hours. A 5 mol/L sodium hydroxide aqueous solution (1.7 mL) was added to the mixture while cooling with water, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with n-hexane/ethyl acetate (1/1). Wash the extract with saturated ammonium chloride aqueous solution, water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~80/20) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy) -3-(Difluoromethyl)aniline (0.330 g). To a mixture of the obtained compound (0.330 g) and ethyl acetate (3 mL), pyridine (0.093 g) and trifluoroacetic anhydride (0.246 g) were added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Methanol (0.029 g) and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Methyl iodide (0.192 g) and potassium carbonate (0.249 g) were added to a mixture of the residue and DMF (1.5 mL), and the mixture was stirred at room temperature for 1 hour. Water, ethyl acetate and n-hexane were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. A 5 mol/L sodium hydroxide aqueous solution (0.36 mL) was added to a mixture of the residue, methanol (1.5 mL) and THF (1.5 mL), and the mixture was stirred at 60°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~80/20) to obtain the title compound (0.300 g).

Reference Example F-8 (3R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-(difluoromethyl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one In an atmosphere of hydrogen, to a mixture of zinc (0.113 g) and DMF (1 mL), (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.389 g) was added, and the mixture was stirred at room temperature for 1 hour. A mixture of Reference Example F-7 (0.300 g) and DMF (1 mL), palladium (II) acetate (0.009 g), and Xphos (0.038 g) were added to the reaction mixture, and the mixture was stirred at 40°C for 2 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution, water, ethyl acetate, and n-hexane were added to the reaction mixture. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated saline. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Methanesulfonic acid (0.227 g) was added to the mixture of the residue, toluene (1 mL) and ethanol (0.5 mL), and stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water, toluene and ethyl acetate were added to the residue for separation. The aqueous layer was separated and ethyl acetate was added, and then a saturated sodium bicarbonate aqueous solution was added under stirring. The organic layer was separated and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.050 g).

Reference Example F-9 Reference Example F-9 was synthesized by the same method as Reference Example F-7, using 4-bromo-2-fluoro-1-(fluoromethyl)benzene instead of 4-bromo-1-(difluoromethyl)-2-fluorobenzene.

Reference Example F-10 Reference Example F-9 was used instead of Reference Example F-1, and Reference Example F-10 was synthesized by the same method as Reference Example F-2.

Reference example F-11 Instead of 4-bromo-1-(difluoromethyl)-2-fluorobenzene, 4-bromo-2-fluoro-1-(trifluoromethyl)benzene was used and synthesized by the same method as Reference Example F-7 Refer to Example F-11.

Reference example F-12 (3R)-3-Amino-8-(2-chloro-5-fluorophenoxy)-1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline -2-one Under an argon environment, to a mixture of zinc (0.256 g) and DMF (3 mL), (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (0.997 g) was added ) and stir at room temperature for 1 hour. A mixture of Reference Example F-11 (0.710 g) and DMF (1.5 mL), palladium (II) acetate (0.020 g), and Xphos (0.085 g) were added to the reaction mixture, and the mixture was stirred at 40° C. for 2 hours. After the reaction mixture was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution, water, ethyl acetate and n-hexane were added. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methanesulfonic acid (0.514 g) was added to a mixture of the residue, toluene (3.5 mL) and ethanol (2 mL), and the mixture was stirred at 70°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, a saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=49/49/2~0/98/2~0/86/14) to obtain the title compound (0.400 g) .

Reference example F-13 Instead of 4-bromo-1-(difluoromethyl)-2-fluorobenzene, 4-bromo-1-(1,1-difluoroethyl)-2-fluorobenzene was used by comparing it with Reference Example F-7 Reference example F-13 was synthesized using the same method.

Reference example F-14 Reference Example F-13 was used instead of Reference Example F-11, and Reference Example F-14 was synthesized by the same method as Reference Example F-12.

Reference Example F-15 Reference Example F-15 was synthesized by the same method as Reference Example F-7, using 4-bromo-1-ethyl-2-fluorobenzene instead of 4-bromo-1-(difluoromethyl)-2-fluorobenzene.

Reference Example F-16 Reference Example F-15 was used instead of Reference Example F-11, and Reference Example F-16 was synthesized by the same method as Reference Example F-12.

Reference example G-1 2-Bromo-6-(1-(2-chlorophenyl)vinyl)-N-methylaniline To a mixture of 1-chloro-2-iodobenzene (0.715 g) and THF (3.7 mL), add isopropyl magnesium chloride (2.0 mol/L in THF) (1.5 mL) at -40°C, and stir at 0°C for 45 minute. A mixture of 3-bromo-2-nitrobenzaldehyde (0.345 g) and THF (3.7 mL) was added to the reaction mixture at -40°C, stirred at the same temperature for 10 minutes, and stirred at 0°C for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue, ethanol (8.2 mL) and water (2.7 mL), iron powder (0.419 g) and ammonium chloride (2.01 g) were added, stirred at 80°C for 2 hours, and then allowed to stand at room temperature for 13 hours. The reaction mixture was stirred at 80°C for 1 hour. After the reaction mixture was cooled to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in n-hexane, and the solid was filtered. The obtained solid was dried under reduced pressure to obtain (2-amino-3-bromophenyl)(2-chlorophenyl)methanol (0.351 g). Manganese dioxide (0.348 g) was added to a mixture of the obtained compound (0.250 g) and DCM (7.3 mL), and the mixture was stirred at room temperature for 2.5 hours and at 35°C for 17 hours. After the reaction mixture was cooled to room temperature, it was filtered through celite. The filtrate was concentrated under reduced pressure to obtain 2-bromo-6-(2-chlorobenzoyl)aniline (0.247 g). Under an argon environment, to a mixture of the obtained compound (0.231 g) and diethyl ether (2.5 mL), methylmagnesium bromide (3.0 mol/L in diethyl ether) (0.52 mL) was added under ice cooling. Stir at the same temperature for 15 minutes and at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 1-(2-amino-3-bromophenyl)-1-( 2-Chlorophenyl)ethan-1-ol (0.247 g). To a mixture of the obtained compound (0.195 g) and 1,2-dichloroethane (3 mL), trifluoroboron diethyl ether complex (0.127 g) and triethylsilane (0.174 g) were added, and the mixture was heated at 70 °C for 2 hours and at 50 °C for 15 hours. A 5 mol/L sodium hydroxide aqueous solution (0.18 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 2-bromo-6-(1-(2-chlorophenyl)vinyl). )aniline (0.171 g). To a mixture of the obtained compound (0.171 g) and THF (1.7 mL), methyllithium (1.04 mol/L in diethyl ether) (0.59 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.094 g) was added to the reaction mixture at -78°C, stirred at the same temperature for 10 minutes, and stirred at 0°C for 1.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.168 g).

Reference example G-2 Reference Example G-1 was used instead of Reference Example F-1, and Reference Example G-2 was synthesized by the same method as Reference Example F-2.

Reference example G-3 2-Bromo-N-methyl-6-(1-(2-(trifluoromethyl)phenyl)vinyl)aniline To a mixture of 1-iodo-2-(trifluoromethyl)benzene (0.710 g) and THF (3 mL), add isopropylmagnesium chloride (2.0 mol/L in THF) (1.3 mL) at -40°C. Stir at 0°C for 30 minutes. A mixture of 3-bromo-2-nitrobenzaldehyde (0.300 g) and THF (3 mL) was added to the reaction mixture at -40°C, stirred at the same temperature for 10 minutes, and stirred at 0°C for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue, ethanol (3 mL) and water (1 mL), iron powder (0.365 g) and ammonium chloride (1.75 g) were added, and the mixture was stirred at 80°C for 1.5 hours. After the reaction mixture was cooled to room temperature, it was filtered through celite. After adding water to the filtrate, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~75/25) to obtain (2-amino-3-bromophenyl)(2-(trifluoro Methyl)phenyl)methanol (0.286 g). Manganese dioxide (0.359 g) was added to a mixture of the obtained compound (0.286 g) and 1,2-dichloroethane (6 mL), and the mixture was stirred at 50°C for 3 hours. After the reaction mixture was cooled to room temperature, it was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=100/0~80/20) to obtain 2-bromo-6-(2-( Trifluoromethyl)benzyl)aniline (0.224 g). To a mixture of the obtained compound (0.224 g) and THF (3 mL), methylmagnesium bromide (3.0 mol/L in THF) (0.65 mL) was added under ice cooling, and the mixture was stirred at room temperature for 0.5 hours. Methyl magnesium bromide (3.0 mol/L in THF) (0.65 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 3 hours. Methyl magnesium bromide (3.0 mol/L in THF) (0.65 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 10 hours. Add saturated aqueous ammonium chloride solution and water to the reaction mixture, and stir at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~75/25) to obtain 1-(2-amino-3-bromophenyl)-1-( 2-(Trifluoromethyl)phenyl)ethan-1-ol (0.187 g). To a mixture of the obtained compound (0.187 g) and 1,2-dichloroethane (3 mL), TFA (0.592 g) and triethylsilane (0.121 g) were added, and the mixture was stirred at 60°C for 1 hour. A 5 mol/L sodium hydroxide aqueous solution (1.0 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 2-bromo-6-(1-(2-(trifluoromethyl)) Phenyl)vinyl)aniline (0.138 g). To a mixture of the obtained compound (0.138 g) and THF (3 mL), methyllithium (3.1 mol/L in diethoxymethane) (0.14 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.069 g) was added to the reaction mixture at -78°C, stirred at the same temperature for 10 minutes, and stirred at 0°C for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~90/10) to obtain the title compound (0.102 g).

Reference Example G-4 Reference Example G-3 was used instead of Reference Example D-9, and Reference Example G-4 was synthesized by the same method as Reference Example D-10.

Reference example G-5 2-Bromo-6-(1-(2-chloro-5-fluorophenyl)vinyl)-N-methylaniline To a mixture of 1-chloro-4-fluoro-2-iodobenzene (0.719 g) and THF (3 mL), add isopropylmagnesium chloride (2.0 mol/L in THF) (1.4 mL) at -40°C. Stir at 0°C for 0.5 hours. A mixture of 1-(2-amino-3-bromophenyl)ethan-1-one (0.300 g) and THF (3 mL) was added to the reaction mixture at -40°C, stirred at 0°C for 1 hour, and Stir at room temperature for 12 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5~70/30) to obtain 1-(2-amino-3-bromophenyl)-1-( 2-Chloro-5-fluorophenyl)ethan-1-ol (0.360 g). To a mixture of the obtained compound (0.360 g) and 1,2-dichloroethane (4 mL), TFA (1.19 g) and triethylsilane (0.243 g) were added, stirred at room temperature for 1 hour, and further stirred at 70°C 3 hours. A 5 mol/L sodium hydroxide aqueous solution (2.2 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain 2-bromo-6-(1-(2-chloro-5-fluorophenyl)vinyl). )aniline (0.320 g). To a mixture of the obtained compound (0.320 g) and THF (5 mL), methyllithium (3.1 mol/L in diethoxymethane) (0.35 mL) was added at -78°C, and the mixture was stirred at the same temperature for 0.5 hours. Methyl iodide (0.167g) was added to the mixture at -78°C, stirred at the same temperature for 10 minutes, and stirred at 0°C for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2~85/15) to obtain the title compound (0.244 g).

Reference Example G-6 Reference Example G-5 was used instead of Reference Example D-15, and Reference Example G-6 was synthesized by the same method as Reference Example D-16.

The structural formulas of the reference examples are shown in the following table.

[Table 1] [Table 2] [table 3] [Table 4] [table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

Example 1 2-(1-Methyl-2-pendantoxy-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)acetamide To a mixture of Reference Example A-3 (0.040 g) and THF (2 mL), LDA (1.09 mol/L in THF/n-hexane) (0.188 mL) was added at -78°C, and stirred at the same temperature for 30 minutes. To the reaction mixture was added tert-butyl bromoacetate (0.062 g) at -78°C, stirred at the same temperature for 30 minutes, and further stirred under ice-cooling for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~2/98) to obtain 2-(1-methyl-2-side oxy-8-phenoxy) Tert-butyl-1,2,3,4-tetrahydroquinolin-3-yl)acetate (0.032 g). A mixture of the obtained compound (0.032 g) and hydrogen chloride (4 mol/L in 1,4-dioxane) (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. TEA (0.045 g), HATU (0.044 g) and ammonia (2 mol/L in methanol) (0.090 mL) were added to the mixture of the residue and DCM (2 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=90/10/0~0/100/0~0/49/51) to obtain the title compound (0.016 g) .

Example 2 (1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example A-3 (0.100 g) and THF (2 mL), LDA (1.09 mol/L in THF/n-hexane) (0.905 mL) was added at -78°C, and stirred at the same temperature for 30 minutes. DPPA (0.272 g) was added to the reaction mixture at -78°C, and stirred at the same temperature for 30 minutes. A mixture of Boc ₂ O (0.172 g) and THF (0.5 mL) was added to the reaction mixture at -78°C, and stirred at the same temperature for 30 minutes, and stirred under ice cooling for 30 minutes. The reaction mixture was stirred at room temperature for 15 minutes and at 50°C for 30 minutes. After the reaction mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~66/34) to obtain (1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (0.125 g). A mixture of the obtained compound (0.125 g) and hydrogen chloride (4 mol/L in 1,4-dioxane) (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. 3-Amino-1-methyl-8-phenoxy-3,4-dihydroxyquinolin-2(1H)-one hydrochloride (0.114 g) was obtained. TEA (0.017 g) and trimethylsilyl isocyanate (0.057 g) were added to a mixture of the obtained compound (0.025 g) and THF (1 mL), and the mixture was stirred at room temperature for 1 hour. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water/MeCN = 70/30~10/90) to obtain the title compound (0.010 g).

Example 3 (8-(2-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example A-5 (0.050 g) and THF (2 mL), LDA (1.09 mol/L in THF/n-hexane) (0.220 mL) was added at -78°C, and stirred at the same temperature for 30 minutes. DPPA (0.127 g) was added to the reaction mixture at -78°C, and stirred at the same temperature for 30 minutes. A mixture of Boc ₂ O (0.080 g) and THF (0.5 mL) was added to the reaction mixture at -78°C, and stirred at the same temperature for 30 minutes, and stirred under ice cooling for 30 minutes. The reaction mixture was stirred at room temperature for 15 minutes and at 50°C for 30 minutes. After the reaction mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 76/24~41/59) to obtain (8-(2-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (0.065 g). A mixture of the obtained compound (0.065 g) and hydrogen chloride (4 mol/L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The mixture of the residue and methanol was passed through APS, and the filtrate was concentrated under reduced pressure. A mixture of potassium cyanate (0.018 g) and water (0.1 mL) and methanesulfonic acid (0.018 g) were added to the mixture of the residue and THF (1 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 90/10/0~0/100/0~0/62/38) to obtain the title compound (0.028 g).

Example 4 (8-(3-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example A-7 (0.075 g) and THF (2 mL), LDA (1.09 mol/L in THF/n-hexane) (0.330 mL) was added at -78°C, and stirred at the same temperature for 30 minutes. DPPA (0.190 g) was added to the reaction mixture at -78°C, and stirred at the same temperature for 30 minutes. A mixture of Boc ₂ O (0.121 g) and THF (0.5 mL) was added to the reaction mixture at -78°C, and stirred at the same temperature for 30 minutes, and stirred under ice cooling for 30 minutes. The reaction mixture was stirred at room temperature for 15 minutes and at 50°C for 30 minutes. After the reaction mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10~41/59) to obtain (8-(3-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (0.039 g). A mixture of the obtained compound (0.039 g) and hydrogen chloride (4 mol/L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The mixture of the residue and methanol was passed through APS, and the eluent was concentrated under reduced pressure. A mixture of potassium cyanate (0.010 g) and water (0.1 mL) and methanesulfonic acid (0.010 g) were added to the mixture of the residue and THF (1 mL), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The mixture of the residue and methanol was passed through APS, and the eluent was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water/MeCN=70/30~10/90) to obtain the title compound (0.016 g).

Example 5 (1-methyl-2-oxo-8-(3-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example A-9 (0.607 g) and THF (2 mL), LDA (1.09 mol/L in THF/n-hexane) (2.25 mL) was added at -78°C, and stirred at the same temperature for 30 minutes. DPPA (1.04 g) was added to the reaction mixture at -78°C, and stirred at the same temperature for 30 minutes. A mixture of Boc ₂ O (0.825 g) and THF (0.5 mL) was added to the reaction mixture at -78°C, and stirred at the same temperature for 30 minutes, and stirred for 30 minutes under ice cooling. The reaction mixture was stirred at room temperature for 15 minutes and at 50°C for 30 minutes. After the reaction mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5~67/33) to obtain (1-methyl-2-oxo-8-(3-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (0.830 g). A mixture of the obtained compound (0.050 g) and hydrogen chloride (4 mol/L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The mixture of the residue and methanol was passed through APS, and the eluate was concentrated under reduced pressure. A mixture of potassium isocyanide (0.012 g) and water (0.1 mL) and methanesulfonic acid (0.011 g) were added to the mixture of the residue and THF (1 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The mixture of the residue and methanol was passed through APS, and the eluate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 100/0 to 80/20) to give the title compound (0.030 g).

Example 6 (8-(3-chlorophenoxy)-1-methyl-2-side oxy-1,2,3,4-tetrahydroquinolin-3-yl)urea vs. Reference Example A-11 (0.345 g) and THF (5 mL), add LDA (1.09 mol/L in THF/n-hexane) (1.32 mL) at -78°C, and stir at the same temperature for 30 minutes. DPPA (0.660 g) was added to the reaction mixture at -78°C, and stirred at the same temperature for 30 minutes. A mixture of Boc ₂ O (0.523 g) and THF (0.5 mL) was added to the mixture at -78°C, stirred at the same temperature for 30 minutes, and stirred under ice-cooling for 30 minutes. The reaction mixture was stirred at room temperature for 15 minutes and at 50°C for 30 minutes. After the reaction mixture was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0~73/27) to obtain N-(8-(3-chlorophenoxy)-1-methyl -2-Pendantoxy-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (0.378 g). A mixture of the obtained compound (0.065 g) and hydrogen chloride (4 mol/L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The mixture of the residue and methanol was passed through APS, and the eluate was concentrated under reduced pressure. A mixture of potassium cyanate (0.017 g) and water (0.1 mL) and methylsulfonic acid (0.017 g) were added to the mixture of the residue and THF (1 mL), and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium bicarbonate solution and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in diethyl ether, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.028 g).

Example 7 Reference Example A-13 was used instead of Reference Example A-5, and Example 7 was synthesized by the same method as Example 3.

Example 8 Reference Example A-15 was used instead of Reference Example A-11, and Example 8 was synthesized by the same method as Example 6.

Example 9 (1-methyl-2-side oxy-8-((3-(trifluoromethyl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinoline- 3-yl) urea: To the mixture of Reference Example A-16 (0.240 g) and THF (2 mL), add LDA (1.09 mol/L in THF/n-hexane) (1.7 mL) at -78°C, and add it at the same temperature Stir for 30 minutes. DPPA (0.512 g) was added to the reaction mixture at -78°C, and stirred at the same temperature for 1 hour. A mixture of Boc ₂ O (0.325 g) and THF (1 mL) was added to the reaction mixture at -78°C, stirred at the same temperature for 10 minutes, and then stirred under ice-cooling for 1 hour. After adding water (3 mL) to the reaction mixture under ice-cooling, the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride solution and ethyl acetate were added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with Method A (elution solvent: n-hexane/ethyl acetate = 90/10~60/40) to obtain (1-methyl-2-side oxy-8-((3-(trifluoromethyl) ((yl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (0.091 g). To a mixture of the obtained compound (0.090 g) and DCM (1 mL), TFA (0.469 g) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. 1 mol/L sodium hydroxide aqueous solution (5 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Potassium isocyanate (0.022 g) and methylsulfonic acid (0.022 g) were added to a mixture of the residue, water (0.037 g) and THF (1 mL), and the mixture was stirred at room temperature for 5 hours. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The insoluble matter was filtered off, and the obtained solid was washed with water and MTBE and dried under reduced pressure to obtain the title compound (0.045 g).

Example 10 ((3R)-1-methyl-2-oxo-8-(2-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-2 (0.080 g) and THF (1 mL), potassium cyanate (0.029 g), water (0.043 g) and methanesulfonic acid (0.025 g) were added and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2~0/98/2~0/86/14) and then by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2~0/98/2~0/86/14) to obtain the title compound (0.040 g).

Example 11 ((3R)-8-(2-methoxyphenoxy)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To the mixture of Reference Example B-4 (0.173g) and THF (1 mL), a mixture of potassium cyanate (0.061 g) and water (0.1 mL) and methylsulfonic acid (0.061 g) were added, and the mixture was stirred at room temperature. 14 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and diethyl ether. The insoluble matter was filtered off, and the obtained solid was dried under reduced pressure to obtain the title compound (0.109 g).

Example 12 ((3R)-8-(3-cyanophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-6 (0.504 g), THF (5 mL) and water (0.5 mL), potassium cyanate (0.184 g) and acetic acid (0.108 g) were added and stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was suspended in DCM and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.068 g).

Example 13~Example 15 Instead of Reference Example B-4, corresponding raw materials were used respectively, and Examples 13 to 15 were synthesized by the same method as Example 11.

Example 16 ((3R)-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-14 (0.050 g) and THF (2 mL), a mixture of potassium cyanate (0.016 g) and water (0.1 mL), and methanesulfonic acid (0.018 g) were added and stirred at room temperature for 14 hours. A saturated aqueous sodium bicarbonate solution and diethyl ether were added to the reaction mixture. The insoluble matter was filtered off and the obtained solid was dried under reduced pressure to obtain the title compound (0.031 g).

Example 17 ((3R)-1-methyl-2-sideoxy-8-(2-(prop-2-yl)phenoxy)-1,2,3,4-tetrahydroquinolin-3-yl) Urea To a mixture of Reference Example B-16 (0.273 g), THF (3 mL) and water (0.3 mL), potassium cyanate (0.095 g) and acetic acid (0.055 g) were added, and the mixture was stirred at room temperature for 1.5 hours. Water and diethyl ether were added to the reaction mixture. The mixture was extracted with diethyl ether, and the extract was concentrated under reduced pressure. The residue was suspended in diethyl ether, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.233 g).

Example 18 ((3R)-8-(2-(Difluoromethyl)phenoxy)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-18 (0.108 g), THF (1 mL) and water (0.1 mL), potassium cyanate (0.037 g) and acetic acid (0.021 g) were added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture. The insoluble matter was filtered off, and the obtained solid was dried under reduced pressure to obtain the title compound (0.091 g).

Example 19 ((3R)-8-(2-chlorophenoxy)-7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-20 (0.278 g) and THF (2 mL), a mixture of potassium cyanate (0.098 g) and water (0.1 mL), and acetic acid (0.062 g) were added and stirred at room temperature for 14 hours. A saturated aqueous sodium bicarbonate solution and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Diethyl ether was added to the residue. The insoluble matter was filtered off, and the obtained solid was dried under reduced pressure to obtain the title compound (0.209 g).

Example 20 ((3R)-8-(2-chloro-4-fluorophenoxy)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To the mixture of Reference Example B-22 (0.295 g) and THF (2 mL), a mixture of potassium cyanate (0.104 g) and water (0.1 mL) and acetic acid (0.066 g) were added, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium bicarbonate solution and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.220 g).

Example 21 ((3R)-8-(5-fluoro-2-(trifluoromethyl)phenoxy)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinoline-3 -base) urea To a mixture of Reference Example B-24 (0.038 g) and THF (0.5 mL), potassium cyanate (0.011 g), water (0.019 g) and methylsulfonic acid (0.011 g) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=49/49/2~0/98/2~0/86/14), and then subjected to APS column chromatography. Method (elution solvent: ethyl acetate/methanol = 98/2~88/12) was purified to obtain the title compound (0.013 g).

Example 22 ((3R)-7-chloro-8-(2-chlorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-26 (0.038 g) and THF (0.5 mL), potassium cyanate (0.012 g), water (0.020 g) and methanesulfonic acid (0.011 g) were added and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in diethyl ether, and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.018 g).

Example 23 ((3R)-7-chloro-8-(2-fluorophenoxy)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-28 (0.044 g) and THF (0.5 mL), potassium cyanate (0.014 g), water (0.025 g) and methylsulfonic acid (0.014 g) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=49/49/2~0/98/2~0/86/14) to obtain the title compound (0.042 g) .

Example 24 ((3R)-8-(3-(difluoromethoxy)phenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-30 (0.188 g), THF (2 mL) and water (0.2 mL), potassium cyanate (0.060 g) and acetic acid (0.036 g) were added and stirred at room temperature for 1.5 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.175 g).

Example 25 Example 25 was synthesized by the same method as Example 23, using Reference Example B-32 instead of Reference Example B-28.

Example 26 ((3R)-7-chloro-8-(3fluorophenoxy)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-34 (0.043 g) and THF (0.5 mL), potassium cyanate (0.014 g), water (0.024 g) and methylsulfonic acid (0.014 g) were added, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=49/49/2~0/98/2~0/86/14) to obtain the title compound (0.042 g) .

Example 27 ((3R)-7-chloro-8-(2-(difluoromethyl)phenoxy)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinoline-3 -base) urea To a mixture of Reference Example B-36 (0.027 g) and THF (0.5 mL), potassium cyanate (0.008 g), water (0.014 g) and methylsulfonic acid (0.008 g) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=49/49/2~0/98/2~0/86/14), followed by silica gel column chromatography. Method (elution solvent: n-hexane/ethyl acetate/methanol=49/49/2~0/98/2~0/86/14) was purified to obtain the title compound (0.015 g).

Example 28 ((3R)-8-(2-(difluoromethyl)-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-38 (0.025 g), THF (1 mL) and water (0.1 mL), potassium cyanate (0.008 g) and acetic acid (0.005 g) were added and stirred at room temperature for 15 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.011 g).

Example 29 Example 29 was synthesized by the same method as Example 24, using Reference Example B-40 instead of Reference Example B-30.

Example 30 ((3R)-8-(2-chloro-5-methoxyphenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-42 (0.133 g) and THF (2 mL), a mixture of potassium cyanate (0.045 g) and water (0.1 mL), and acetic acid (0.029 g) were added and stirred at room temperature for 14 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water/MeCN = 70/30~10/90) to obtain the title compound (0.056 g).

Example 31 ((3R)-8-(2-chlorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-44 (0.074 g) and THF (2 mL), a mixture of potassium cyanate (0.027 g) and water (0.1 mL), and acetic acid (0.017 g) were added and stirred at room temperature for 14 hours. Water and MTBE were added to the reaction mixture. The insoluble matter was filtered off, and the obtained solid was dried under reduced pressure to obtain the title compound (0.031 g).

Example 32 ((3R)-7-(Benzyloxy)-8-(2-chlorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-46 (0.100 g) and THF (2 mL), a mixture of potassium cyanate (0.028 g) and water (0.1 mL), and acetic acid (0.018 g) were added and stirred at room temperature for 14 hours. Water and MTBE were added to the reaction mixture. The insoluble matter was filtered off, and the obtained solid was purified by ODS column chromatography (elution solvent: water/MeCN=70/30~10/90) to obtain the title compound (0.042 g).

Example 33 ((3R)-8-(2-chlorophenoxy)-7-hydroxy-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Example 32 (0.034 g), THF (0.5 mL) and methanol (0.5 mL), 10% Pd/C (0.008 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water/MeCN=70/30~10/90) to obtain the title compound (0.016 g).

Example 34 ((3R)-8-(2-chlorophenoxy)-1-ethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-48 (0.138 g) and THF (2 mL), a mixture of potassium cyanate (0.053 g) and water (0.1 mL), and acetic acid (0.037 g) were added and stirred at room temperature for 14 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.036 g).

Example 35 ((3R)-8-(2-chloro-4,5-difluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-50 (0.068 g) and THF (1 mL), potassium cyanate (0.021 g), water (0.036 g) and methanesulfonic acid (0.020 g) were added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2~0/98/2~0/86/14), and then purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2~0/98/2~0/86/14) and ODS column chromatography (elution solvent: water/MeCN = 70/30~10/90) to obtain the title compound (0.018 g).

Example 36 Example 36 was synthesized by the same method as Example 10, using Reference Example B-52 instead of Reference Example B-2.

Example 37 ((3R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-54 (0.003 g) and THF (0.2 mL), potassium cyanate (0.001 g), water (0.002 g) and methanesulfonic acid (0.001 g) were added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2~0/98/2~0/86/14) to obtain the title compound (0.003 g).

Example 38 ((3R)-8-(2-(difluoromethyl)phenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-56 (0.080 g), THF (1 mL) and water (0.1 mL), potassium cyanate (0.027 g) and acetic acid (0.017 g) were added and stirred at room temperature for 3.5 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.070 g).

Example 39 ((3R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-58 (0.118 g), THF (1 mL) and water (0.1 mL), potassium cyanate (0.039 g) and acetic acid (0.025 g) were added and stirred at room temperature for 3.5 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.062 g).

Example 40 ((3R)-8-(2-chlorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-60 (0.370 g) and THF (2.5 mL), potassium cyanate (0.129 g), water (0.220 g) and methanesulfonic acid (0.123 g) were added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution, water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2~0/98/2~0/86/14) to obtain the title compound (0.390 g).

Example 41 Reference Example B-62 was used instead of Reference Example B-28, and Example 41 was synthesized by the same method as Example 23.

Example 42 ((3R)-8-(cyclopentyloxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-64 (0.100 g) and THF (1 mL), potassium cyanate (0.041 g), water (0.069 g) and methanesulfonic acid (0.039 g) were added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution, water, DCM and ethyl acetate were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Ethyl acetate and water were added to the residue. Insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.076 g).

Example 43 ((3R)-8-(2-(difluoromethyl)phenoxy)-7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-66 (0.035 g) and THF (2 mL), a mixture of potassium cyanate (0.013 g) and water (0.1 mL), and acetic acid (0.009 g) were added and stirred at room temperature for 14 hours. Water and MTBE were added to the reaction mixture. Insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.030 g).

Example 44 ((3R)-8-(2-chloro-5-fluorophenoxy)-7-fluoro-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinoline-3- base) urea To the mixture of Reference Example B-68 (0.070 g) and THF (2 mL), a mixture of potassium cyanate (0.025 g) and water (0.1 mL) and acetic acid (0.017 g) were added, and the mixture was stirred at room temperature for 14 hours. Water and MTBE were added to the reaction mixture. Filter out the insoluble matter. The obtained solid was dried under reduced pressure to obtain the title compound (0.052 g).

Example 45 ((3R)-8-(2-Fluorophenoxy)-1,7-dimethyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To the mixture of Reference Example B-70 (0.031 g) and THF (2 mL), a mixture of potassium cyanate (0.013 g) and water (0.1 mL) and acetic acid (0.009 g) were added, and the mixture was stirred at room temperature for 14 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.030 g).

Example 46 ((3R)-8-(3-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-72 (0.065 g) and THF (2 mL), a mixture of potassium cyanate (0.026 g) and water (0.1 mL), and acetic acid (0.018 g) were added and stirred at room temperature for 14 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.027 g).

Example 47 ((3R)-1-methyl-8-(2-methylphenoxy)-2-pendantoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-74 (0.290 g) and THF (3 mL), potassium cyanate (0.108 g), water (0.185 g) and methylsulfonic acid (0.104 g) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and ethyl acetate. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was suspended in MTBE, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.210 g).

Example 48 (3R)-8-(5-fluoro-2-methylphenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-76 (0.220 g) and THF (2 mL), potassium cyanate (0.077 g), water (0.132 g) and methanesulfonic acid (0.074 g) were added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution, water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was suspended in MTBE and the insoluble matter was filtered out. The obtained solid was dried under reduced pressure to obtain the title compound (0.190 g).

Example 49 ((3R)-8-(2-Fluorophenoxy)-1-methyl-2-pendantoxy-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-3 -base) urea To a mixture of Reference Example C-3 (0.026 g) and THF (1 mL), potassium cyanate (0.008 g), water (0.013 g) and methylsulfonic acid (0.007 g) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=50/50/0~0/100/0~0/90/10) to obtain the title compound (0.025 g) .

Example 50 ((3R)-8-(2,5-difluorophenoxy)-1,7-dimethyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl) Urea To a mixture of Reference Example B-78 (0.274 g), THF (1.5 mL) and methanol (1.0 mL), potassium cyanate (0.094 g), water (0.278 g) and acetic acid (0.065 g) were added, and the mixture was stirred at room temperature. 1 hour. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE and the solid was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.242 g).

Example 51 ((3R)-8-((2-chlorophenyl)methyl)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-2 (0.120 g) and THF (1 mL), potassium cyanate (0.042 g), water (0.072 g) and methylsulfonic acid (0.040 g) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.096 g).

Example 52 ((3R)-8-((2-chloro-5-fluorophenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-4 (0.100 g), THF (0.8 mL) and water (0.057 mL), potassium cyanate (0.033 g) and methanesulfonic acid (0.032 g) were added and stirred at room temperature for 2.5 hours. Methanesulfonic acid (0.003 g) was added to the reaction mixture and stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate and the insoluble matter was filtered out. The obtained solid was dried under reduced pressure to obtain the title compound (0.055 g).

Example 53 ((3R)-1-Methyl-2-Pendantoxy-8-((2-(trifluoromethyl)phenyl)methyl)-1,2,3,4-tetrahydroquinoline-3- base) urea To a mixture of Reference Example D-6 (0.100 g), THF (0.8 mL) and water (0.054 mL), potassium cyanate (0.032 g) and methylsulfonic acid (0.030 g) were added, and the mixture was stirred at room temperature for 2.5 hours. Methanesulfonic acid (0.003 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica column chromatography (elution solvent: DCM/methanol=100/0~90/10). 2 mol/L hydrochloric acid was added to the obtained target substance, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the residue. The resulting solid was filtered and dried under reduced pressure to obtain the title compound (0.026 g).

Example 54 ((3R)-1-methyl-8-((2-methylphenyl)methyl)-2-side oxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-8 (0.046 g), THF (0.5 mL) and water (0.030 mL), potassium cyanate (0.017 g) and methylsulfonic acid (0.017 g) were added, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.012 g).

Example 55 ((3R)-8-((2-(difluoromethyl)phenyl)methyl)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinoline-3- base) urea To a mixture of Reference Example D-10 (0.032 g), THF (1 mL) and water (0.018 mL), potassium cyanate (0.011 g) and methylsulfonic acid (0.010 g) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate/n-hexane (1/1), and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.018 g).

Example 56 ((3R)-8-((2-chloro-5-fluorophenyl)methyl)-7-fluoro-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinoline -3-yl)urea To a mixture of Reference Example D-12 (0.006 g), THF (1 mL) and water (0.003 mL), potassium cyanate (0.002 g) and methylsulfonic acid (0.002 g) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: DCM/methanol=100/0~90/10) to obtain the title compound (0.004 g).

Example 57 ((3R)-7-chloro-8-((2-chloro-5-fluorophenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-14 (0.036 g), THF (0.3 mL) and water (0.2 mL), potassium cyanate (0.012 g), water (0.035 mL) and acetic acid (0.008 g) were added and stirred at room temperature for 1.5 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the residue. The resulting solid was filtered. The resulting solid was dried under reduced pressure to obtain the title compound (0.004 g).

Example 58 ((3R)-8-((2-chlorophenyl)methyl)-1,7-dimethyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl) Urea To a mixture of Reference Example D-16 (0.009 g), THF (0.3 mL) and water (0.005 mL), potassium cyanate (0.003 g) and methylsulfonic acid (0.003 g) were added, and the mixture was stirred at room temperature for 20 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.004 g).

Example 59 ((3R)-8-((2-chloro-5-fluorophenyl)methyl)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-18 (0.008 g), THF (0.3 mL) and water (0.004 mL), potassium cyanate (0.003 g) and methanesulfonic acid (0.002 g) were added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.002 g).

Example 60 (3R)-8-((2-chlorophenyl)methyl)-7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-20 (0.049 g), THF (1 mL) and water (0.028 mL), potassium cyanate (0.016 g) and methanesulfonic acid (0.016 g) were added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate/n-hexane (1/1), and the insoluble matter was filtered out. The obtained solid was dried under reduced pressure to obtain the title compound (0.018 g).

Example 61 ((3R)-7-Fluoro-1-methyl-2-pendantoxy-8-((2-(trifluoromethyl)phenyl)methyl)-1,2,3,4-tetrahydroquin Phin-3-yl)urea To a mixture of Reference Example D-22 (0.028 g), THF (1 mL) and water (0.014 mL), potassium cyanate (0.008 g) and methylsulfonic acid (0.008 g) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate/n-hexane (1/1), and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.014 g).

Example 62 ((3R)-7-chloro-8-((2-chlorophenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-24 (0.026 g), THF (1 mL) and water (0.014 mL), potassium cyanate (0.008 g) and methanesulfonic acid (0.008 g) were added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate/n-hexane (1/1), and the insoluble matter was filtered out. The obtained solid was dried under reduced pressure to obtain the title compound (0.013 g).

Example 63 ((3R)-7-fluoro-1-methyl-8-((2-methylphenyl)methyl)-2-side oxy-1,2,3,4-tetrahydroquinoline-3- base) urea To a mixture of Reference Example D-26 (0.040 g), THF (1 mL) and water (0.024 mL), potassium cyanate (0.014 g) and methylsulfonic acid (0.014 g) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate/n-hexane (1/1), and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.026 g).

Example 64 ((3R)-7-chloro-8-((2-fluorophenyl)methyl)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl )urea To the mixture of Reference Example D-28 (0.097 g), THF (0.9 mL) and water (0.6 mL), potassium cyanate (0.037 g), water (0.110 mL) and acetic acid (0.026 g) were added, and the mixture was stirred at room temperature. 17.5 hours. Water was added to the reaction mixture, and insoluble matter was filtered off. The obtained solid was suspended in MTBE and filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.073 g).

Example 65 to Example 67 Replacing Reference Example D-28 with corresponding raw materials, Example 65 to Example 67 were synthesized by the same method as Example 64.

Example 68 (3R)-8-((5-fluoro-2-methylphenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-36 (0.030 g), THF (0.3 mL) and water (0.018 mL), potassium cyanate (0.011 g) and methanesulfonic acid (0.010 g) were added and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.026 g).

Example 69 ((3R)-7-chloro-8-(2,5-difluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-2 (0.084 g), THF (0.48 mL) and methanol (0.32 mL), potassium cyanate (0.030 g), water (0.089 g) and acetic acid (0.021 g) were added and stirred at room temperature for 2 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: DCM/methanol = 100/0~95/5) to obtain the title compound (0.013 g).

Example 70 ((3R)-8-(2-(Difluoromethyl)-5-fluorophenoxy)-1,7-dimethyl-2-sideoxy-1,2,3,4-tetrahydroquin Phin-3-yl)urea To the mixture of Reference Example F-4 (0.005 g), THF (0.3 mL) and methanol (0.2 mL), potassium cyanate (0.002 g), water (0.005 g) and acetic acid (0.001 g) were added, and the mixture was stirred at room temperature. 2 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: DCM/methanol=100/0~90/10) to obtain the title compound (0.002 g).

Example 71 ((3R)-8-(2-chloro-5-fluorophenoxy)-7-(hydroxymethyl)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquin Phin-3-yl)urea To a mixture of Reference Example F-6 (0.270 g) and THF (3.0 mL), potassium cyanate (0.081 g), water (0.139 g) and acetic acid (0.049 g) were added, and the mixture was stirred at room temperature for 21 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, water and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=49/49/2~0/98/2~0/78/22) to obtain the title compound (0.210 g) .

Example 72 (3R)-8-(2-chloro-5-fluorophenoxy)-7-(difluoromethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-8 (0.050 g) and THF (1 mL), potassium cyanate (0.014 g), water (0.024 g) and acetic acid (0.009 g) were added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.035 g).

Example 73 ((3R)-8-(2-chloro-5-fluorophenoxy)-7-(fluoromethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-10 (0.100 g) and THF (1 mL), potassium cyanate (0.030 g), water (0.051 g) and acetic acid (0.018 g) were added and stirred at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution, water, methanol and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE and the insoluble matter was filtered. The obtained solid was dried under reduced pressure to obtain the title compound (0.090 g).

Example 74 ((3R)-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-12 (0.400 g), methanol (1.2 mL) and THF (1.8 mL), potassium cyanate (0.109 g), water (0.371 g) and acetic acid (0.068 g) were added and stirred at room temperature for 3 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2~0/98/2~0/86/14) to obtain the title compound (0.390 g).

Example 75 ((3R)-8-(2-chloro-5-fluorophenoxy)-7-(1,1-difluoroethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-14 (0.250 g), methanol (0.75 mL) and THF (1.1 mL), potassium cyanate (0.069 g), water (0.234 g) and acetic acid (0.043 g) were added and stirred at room temperature for 2 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2~0/98/2~0/86/14) to obtain the title compound (0.200 g).

Example 76 ((3R)-8-(2-chloro-5-fluorophenoxy)-7-ethyl-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-16 (0.480 g), methanol (1.4 mL) and THF (2.2 mL), potassium cyanate (0.145 g), water (0.496 g) and acetic acid (0.091 g) were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture and the insoluble matter was filtered out. The obtained solid was washed with water and MTBE and dried under reduced pressure to obtain the title compound (0.473 g).

Example 77 ((3R)-8-(1-(2-chlorophenyl)ethyl)-1-methyl-2-sideoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To the mixture of Reference Example G-2 (0.024 g), THF (0.3 mL) and methanol (0.2 mL), potassium cyanate (0.009 g), water (0.027 g) and acetic acid (0.006 g) were added, and the mixture was stirred at room temperature. 45 minutes. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water/MeCN=70/30~10/90) to obtain ((3R)-8-(1-(2-chlorophenyl)vinyl)- 1-Methyl-2-pendantoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea (0.015 g). Platinum (IV) oxide (0.003 g) was added to a mixture of the obtained compound (0.014 g) and THF (1 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. Platinum (IV) oxide (0.009 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water/MeCN=70/30~10/90) to obtain the title compound (0.005 g).

Example 78 (3R)-1-methyl-2-oxo-8-(1-(2-(trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-4 (0.013 g), THF (1 mL) and water (0.007 mL), potassium cyanate (0.004 g) and methanesulfonic acid (0.004 g) were added and stirred at room temperature for 10 hours. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: DCM/methanol = 100/0~90/10) to obtain ((3R)-1-methyl-2-oxo-8-(1-(2-(trifluoromethyl)phenyl)vinyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea (0.012 g). 10% Pd/C (0.001 g) was added to the mixture of the obtained compound (0.012 g) and methanol (1 mL), and stirred at room temperature for 12 hours under a hydrogen environment. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: DCM/methanol = 100/0~95/5) and then by ODS column chromatography (elution solvent: water/MeCN = 70/30~10/90) to obtain the title compound (0.005 g).

Example 79 ((3R)-8-(1-(2-chloro-5-fluorophenyl)ethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-6 (0.038 g), THF (0.3 mL) and water (0.021 g), potassium cyanate (0.012 g) and methanesulfonic acid (0.012 g) were added and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution, water and DCM were added to the reaction mixture and stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. 10% Pt/C (0.010 g) was added to the mixture of the residue, methanol (0.5 mL) and THF (0.5 mL), and stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water/MeCN = 70/30~10/90) to obtain the title compound (0.005 g).

Example 80 1-((3R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-3-methylurea To a mixture of Reference Example B-58 (0.036 g), carbonyldiimidazole (0.017 g) and DCM (1 mL), DIPEA (0.069 g) was added and stirred at room temperature for 1 hour. Methylamine (2 mol/L in THF) (0.11 mL) was added to the reaction mixture and stirred at room temperature for 3 hours. Water and DCM were added to the reaction mixture and stirred at room temperature for 5 minutes. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 30/70/0~0/100/0~0/70/30) to obtain the title compound (0.026 g).

Example 81 N-((3R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide To a mixture of Reference Example B-58 (0.100 g), DIPEA (0.077 g) and DCM (1 mL), acetyl chloride (0.030 g) was added under water cooling and stirred at the same temperature for 1 hour. Water was added to the reaction mixture and stirred at room temperature for 5 minutes. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 30/70/0~0/100/0~0/70/30) to obtain the title compound (0.079 g).

Example 82 Example 82 was obtained by the same method as Example 81 except that cyclopropylformate chloride was used instead of acetyl chloride.

Example 83 Example 83 was obtained by the same method as Example 81, using dichloroacetyl chloride instead of acetyl chloride.

Example 84 Example 84 was obtained by the same method as Example 81, except that Reference Example B-14 was used instead of Reference Example B-58, and cyclopropanecarbonyl chloride was used instead of acetyl chloride.

Example 85 N-((3R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-sideoxy-1,2,3,4-tetrahydroquinoline-3 -yl)-3,3,3-trifluoropropamide To the mixture of Reference Example B-58 (0.100 g), 3,3,3-trifluoropropionic acid (0.042 g), HATU (0.125 g) and MeCN (1 mL), add DIPEA (0.046 g) and keep at room temperature Stir for 1 hour. Water and DCM were added to the reaction mixture, and stirred at room temperature for 5 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol=20/80/0~0/100/0~0/70/30), followed by ODS column chromatography. Method (elution solvent: water/MeCN=90/10~10/90) was purified to obtain the title compound (0.074 g).

The structural formulas, physical property values and TSHR antagonistic activity of the examples (see Test Example 1) are shown in the table below.

[Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27]

Test example 1 Determination of antagonistic activity as an indicator of TSH-induced cAMP production in stably expressed human TSHR CHO cells

The gene sequence of human TSHR (reference number NM_000369.2) was inserted into the multiple selection site of pcDNA3.1(+). The prepared plasmid vector was introduced into CHO cells using lipofection to establish CHO cells stably expressing human TSHR. The obtained cells were seeded at 5×10 ⁴ cells/well in a 96-well poly-D-lysine coated plate and cultured in F12 medium containing 10% FBS, 400 μg/mL G418, 50 U/mL penicillin and 50 μg/mL streptomycin at 37°C and 5% CO ² for 1 day. After removing the medium, the cells were washed twice with 100 μL of assay buffer (Hanks' Balanced Salt Solution containing 20 mM HEPES and 1 mM IBMX) per well. 30 μL of assay buffer containing the test compound was added to the wells and incubated at room temperature for 15 minutes. Then, 30 μL of assay buffer containing human TSH (R&D Systems, Inc., final concentration 50 ng/mL) was added and incubated at 37°C for 1 hour. The supernatant was removed, Lysis and Detection Buffer 2 (Cisbio) was added, and the cells were incubated at room temperature for 1 hour to prepare a cell lysate. According to the cAMP Gs According to the instruction manual of HiRange kit (Cisbio), the cell lysate was reacted with d2-labeled cAMP and anti-cAMP Europium Cryptate labeled antibody (Cisbio) in a 384-well white microplate. Then, the fluorescence intensity ratio was measured using a multifunctional microplate analyzer (PHERAstar FSX, BMG LABTECH JAPAN) (measurement wavelength 665 nm/620 nm). The fluorescence intensity ratio of each sample was converted to cAMP content using a standard curve. The cAMP content was converted to a percentage of the control value to calculate the cAMP generation rate. Prism (Graph Pad Software Inc.) was used to plot the cAMP generation rate relative to the test compound concentration and the IC ₅₀ value was calculated. The IC ₅₀ of each test compound is shown above. In the table, IC ₅₀ <0.5 μM: A, 0.5 μM≦IC ₅₀ ＜3.0 μM: B, 3.0 μM≦IC ₅₀ ＜30 μM: C.

As shown above, the compound of the present invention clearly has human TSHR antagonist activity. (Industrial Applicability)

The compound of the present invention or a pharmacologically acceptable salt thereof has TSHR antagonistic activity and therefore can be used as a therapeutic agent for thyroid-related diseases.

Claims (15)

A compound or a pharmacologically acceptable salt thereof is represented by formula (I); [Chemical 1] [wherein, Ring Z is a C _6-10 aryl group, a 5- or 6-membered heteroaryl group, a C _3-8 cycloalkyl group, or a 3-8-membered heterocycloalkyl group; X is -CHR ^x - or -O-; R ^x is a hydrogen atom or a C _1-6 alkyl group; V ¹ is =CR ^{V 1} - or =N-; V ² is =CR ^{V 2} - or =N-; V ³ is =CR ^{V 3} - or =N-; R ^{V 1} , R ^{V 2} , and R ^{V 3} are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen C _1-6 alkyl group, a hydroxyl C _1-6 alkyl group, a C _6-10 aryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkoxy group; W is -CH ₂ - or -NH-; R [ ₀₀₄₃ ] wherein ^R1 is a hydrogen atom or a _C1-6 alkyl group; ^R2 is a halogen atom, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogen _C1-6 alkyl group, a C1-6 alkoxy group, a halogen _C1-6 alkoxy group, a _C6-10 aryl _C1-6 alkyl group or a _C6-10 aryl _C1-6 alkoxy group; n is an integer from 0 to 3; when n is 2 or 3, each ^R2 may be the same or different; ^R3 is a hydrogen atom, a halogen atom, or a _C1-6 alkyl group; ^R4 is a _C1-6 alkyl group, a halogen _C1-6 alkyl group, ^{-NR5R5 '} , or a _C3-8 cycloalkyl group; ^R5 and R5 ^' are independently a hydrogen atom or a _C1-6 alkyl group]. The compound of claim 1 or a pharmacologically acceptable salt thereof, which is represented by formula (II); [Chemical 2] [wherein, Ring Z is a C _6-10 aryl group, a 5- or 6-membered cycloheteroaryl group, a C _3-8 cycloalkyl group, or a 3-8-membered cycloheteroalkyl group; X is -CHR ^x -, or -O-; R ^x is a hydrogen atom, or a C _1-6 alkyl group; V ¹ is =CR ^{V 1} -, or =N-; V ² is =CR ^{V 2} -, or =N-; V ³ is =CR ^{V 3} -, or =N-; R ^{V 1} , R ^{V 2} , and R ^{V 3} are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen C _1-6 alkyl group, a C _6-10 aryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkoxy group; W is -CH ₂ -, or -NH-; R ¹ is a hydrogen atom, or a C [0045] R2 is _{a C1-6} alkyl group; ^R2 is a halogen atom, a cyano group, a hydroxyl group, an _amino group, a _C1-6 alkyl group, a halogen _C1-6 alkyl group, a _C1-6 alkoxy group, a halogen C1-6 alkoxy group, a _C6-10 aryl _C1-6 alkyl group or a _C6-10 aryl _C1-6 alkoxy group; n is an integer from 0 to 3; when n is 2 or 3, each ^R2 may be the same or different from each other; ^R3 is a hydrogen atom, a halogen atom, or a _C1-6 alkyl group]. The compound of claim 2 or a pharmacologically acceptable salt thereof, wherein ^V1 is =CR ^V1 -; ^V2 is =CR ^V2 -; ^V3 is =CR ^V3 -; R ^V1 , R ^V2 , and R ^V3 have the same meanings as in claim 2. The compound of claim 3 or a pharmacologically acceptable salt thereof, wherein ring Z is a C _6-10 aryl group. The compound of claim 2 or a pharmacologically acceptable salt thereof is represented by formula (III); [Chemical 3] [wherein, X is ^-CHRx- , or -O-; ^Rx is a hydrogen atom or a _C1-6 alkyl group; ^RV1 is a hydrogen atom, a halogen atom, a hydroxyl group, a _C1-6 alkyl group, a _C1-6 alkoxy group, a halogen _C1-6 alkyl group, a _C6-10 aryl _C1-6 alkyl group, or a _C6-10 aryl _C1-6 alkoxy group; ^R1 is a hydrogen atom or a _C1-6 alkyl group; ^R2 is a halogen atom, a cyano group, a hydroxyl group, an amino group, a _C1-6 alkyl group, a halogen _C1-6 alkyl group, a _C1-6 alkoxy group, a halogen _C1-6 alkoxy group, a _C6-10 aryl _C1-6 alkyl group, or a _C6-10 aryl _C1-6 alkoxy group; n is an integer from 0 to 3; when n is 2 or 3, each ^R2 may be the same or different from each other]. The compound of claim 5 or its pharmacologically acceptable salt, wherein R ^V1 is a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, or a halogen C _1-6 alkyl group. ; R ¹ is a C _1-6 alkyl group; R ² is a halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _1-6 alkoxy group, or halo C _1-6 alkoxy group. The compound of claim 1 or a pharmacologically acceptable salt thereof is represented by formula (IV); [Chemical 4] [wherein, Ring Z is a C _6-10 aryl group, a 5- or 6-membered heteroaryl group, or a C _3-8 cycloalkyl group; X is -CHR ^x -, or -O-; R ^x is a hydrogen atom, or a C _1-6 alkyl group; ^RV1 is a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group, a halogen C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkoxy group; R ¹ is a C _1-6 alkyl group; R ² is a halogen atom, a cyano group, a C _1-6 alkyl group, a halogen C _1-6 alkyl group, a C _1-6 alkoxy group, or a halogen C _1-6 alkoxy group; n is an integer from 0 to 3; when n is 2 or 3, each R ² may be the same or different from each other]. The compound of claim 7 or a pharmacologically acceptable salt thereof, wherein ring Z is a C _6-10 aryl group. The compound of claim 8 or its pharmacologically acceptable salt, wherein, X is -O-. A compound or a pharmacologically acceptable salt thereof is selected from the group consisting of the following compounds; [Chemistry 5] [Chemistry 6] and [Chemistry 7] The compound of claim 8 or a pharmacologically acceptable salt thereof, wherein X is -CHR ^x -; R ^x has the same meaning as in claim 7. A compound or a pharmacologically acceptable salt thereof selected from the group consisting of the following compounds; [Chemical 8] And [Chemical 9] A pharmaceutical composition containing a compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof, and pharmaceutical additives. The pharmaceutical composition of claim 13 is a pharmaceutical composition for treating thyroid-related diseases. For example, the pharmaceutical composition of claim 14, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.